Alternative titles; symbols
DO: 0060892;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q22 | {Parkinson disease, late-onset, susceptibility to} | 168600 | Autosomal dominant; Multifactorial | 3 | GBA | 606463 |
| 4q23 | {Parkinson disease, susceptibility to} | 168600 | Autosomal dominant; Multifactorial | 3 | ADH1C | 103730 |
| 6q27 | {Parkinson disease, susceptibility to} | 168600 | Autosomal dominant; Multifactorial | 3 | TBP | 600075 |
| 12q24.12 | {Parkinson disease, late-onset, susceptibility to} | 168600 | Autosomal dominant; Multifactorial | 3 | ATXN2 | 601517 |
| 13q21.33 | {Parkinson disease, susceptibility to} | 168600 | Autosomal dominant; Multifactorial | 3 | ATXN8OS | 603680 |
| 14q32.12 | {Parkinson disease, late-onset, susceptibility to} | 168600 | Autosomal dominant; Multifactorial | 3 | ATXN3 | 607047 |
| 17q21.31 | {Parkinson disease, susceptibility to} | 168600 | Autosomal dominant; Multifactorial | 3 | MAPT | 157140 |
A number sign (#) is used with this entry because of evidence that late-onset or sporadic Parkinson disease (PD) can have more than one genetic and/or environmental cause.
Parkinson disease (PD) was first described by James Parkinson in 1817. It is the second most common neurodegenerative disorder after Alzheimer disease (AD; 104300), affecting approximately 1% of the population over age 50 (Polymeropoulos et al., 1996).
Reviews
Warner and Schapira (2003) reviewed the genetic and environmental causes of Parkinson disease. Feany (2004) reviewed the genetics of Parkinson disease and provided a speculative model of interactions among proteins implicated in PD. Lees et al. (2009) provided a review of Parkinson disease, with emphasis on diagnosis, neuropathology, and treatment.
Genetic Heterogeneity of Parkinson Disease
Several loci for autosomal dominant Parkinson disease have been identified, including PARK1 (168601) and PARK4, caused by mutation in or triplication of the alpha-synuclein gene (SNCA; 163890), respectively, on 4q22; PARK5 (191342), caused by mutation in the UCHL1 gene on 4p13; PARK8 (607060), caused by mutation in the LRRK2 gene (609007) on 12q12; PARK11 (607688), caused by mutation in the GIGYF2 gene (612003) on 2q37; PARK13 (610297), caused by mutation in the HTRA2 gene (606441) on 2p13; PARK17 (614203), caused by mutation in the VPS35 gene (601501) on 16q11; PARK18 (614251), caused by mutation in the EIF4G1 gene (600495) on 3q27; PARK22 (616710), caused by mutation in the CHCHD2 gene (616244) on 7p11; and PARK24 (619491), caused by mutation in the PSAP gene (176801) on 10q22.
Several loci for autosomal recessive early-onset Parkinson disease have been identified: PARK2 (600116), caused by mutation in the gene encoding parkin (PRKN, PARK2; 602544) on 6q26; PARK6 (605909), caused by mutation in the PINK1 gene (608309) on 1p36; PARK7 (606324), caused by mutation in the DJ1 gene (PARK7; 602533) on 1p36; PARK14 (612953), caused by mutation in the PLA2G6 gene (603604) on 22q13; PARK15 (260300), caused by mutation in the FBXO7 gene (605648) on 22q12-q13; PARK19A (615528) and PARK19B (see 615528), caused by mutation in the DNAJC6 gene (608375) on 1p32; PARK20 (615530), caused by mutation in the SYNJ1 gene (604297) on 21q22; and PARK23 (616840), caused by mutation in the VPS13C gene (608879) on 15q22; and PARK25 (620482), caused by mutation in the PTPA gene (600756) on 9q34.
PARK3 (602404) has been mapped to chromosome 2p13; PARK10 (606852) has been mapped to chromosome 1p34-p32; PARK16 (613164) has been mapped to chromosome 1q32. See also PARK21 (616361). A locus on the X chromosome has been identified (PARK12; 300557). There is also evidence that mitochondrial mutations may cause or contribute to Parkinson disease (see 556500).
Susceptibility to the development of the more common late-onset form of Parkinson disease has been associated with polymorphisms or mutations in several genes, including GBA (606463), MAPT (157140), MC1R (155555), ADH1C (103730), and genes at the HLA locus (see, e.g., HLA-DRA, 142860). Each of these risk factors independently may have a modest effect on disease development, but together may have a substantial cumulative effect (Hamza et al., 2010).
Susceptibility to PD may also be conferred by expanded trinucleotide repeats in several genes causing other neurologic disorders usually characterized by spinocerebellar ataxia (SCA), including the ATXN2 (601517), ATXN3 (607047), TBP (600075), and ATXN8OS (603680) genes.
The diagnosis of classic idiopathic PD is primarily clinical, with manifestations including resting tremor, muscular rigidity, bradykinesia, and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The disease is progressive and usually has an insidious onset in mid to late adulthood. Pathologic features of classic PD include by a loss of dopaminergic neurons in the substantia nigra (SN) and the presence of Lewy bodies, intracellular inclusions, in surviving neurons in various areas of the brain, particularly the SN (Nussbaum and Polymeropoulos, 1997). Autosomal recessive juvenile Parkinson disease (PARK2; 600116), however, does not have Lewy body pathology (Nussbaum and Polymeropoulos, 1997).
Many other diseases, both genetic and nongenetic, have parkinsonian motor features ('parkinsonism'), which most likely result from loss or dysfunction of the dopaminergic neurons in the SN, but may or may not have Lewy bodies on pathology. Thus, accurate diagnosis may be difficult without pathologic examination. Dementia with Lewy bodies (DLB; 127750) shows parkinsonism with Lewy bodies. However, parkinsonism without Lewy bodies characterizes progressive supranuclear palsy (PSP; 601104), frontotemporal dementia with parkinsonism (600274), autosomal dominant (128230) and recessive (605407) forms of Segawa syndrome, X-linked recessive Filipino type of dystonia (314250), multiple systems atrophy, and cerebrovascular disease.
In a retrospective analysis, Paleacu et al. (2005) found that 76 (32%) of 234 PD patients reported hallucinations. All experienced visual hallucinations, most commonly of human images, and 6 also reported mood congruent auditory hallucinations. The presence of hallucinations was correlated with family history of dementia and lower scores on the Mini-Mental State Examination (MMSE). Neither the dose nor duration of L-DOPA treatment was a significant variable for hallucinations.
Using PET scan, Ballanger et al. (2010) showed that 7 PD patients with visual hallucinations had increased binding to serotonin 2A receptors (HTR2A; 182135) in the ventral visual pathway compared to 7 PD patients without visual hallucinations. Areas of the ventral visual pathway that showed increased HTR2A binding included the bilateral inferooccipital gyrus, the right fusiform gyrus, and the inferotemporal cortex. The findings suggested that abnormalities in serotonin 2A receptor neurotransmission may be involved in the pathogenesis of visual hallucinations in PD.
Using single-photon emission CT with a radiolabeled ligand for several beta-2 (CHRNB2; 118507)-containing nicotinic acetylcholine receptors (nAChR), Fujita et al. (2006) showed that 10 nondemented PD patients had a widespread significant global decrease in nAChRs compared to 15 controls. The most significant decrease was in the thalamus.
Some studies have observed an increased risk of Parkinson disease among individuals with melanoma (155600) (see, e.g., Constantinescu et al., 2007 and Ferreira et al., 2007), suggesting that pigmentation metabolism may be involved in the pathogenesis of PD. From 2 existing study cohorts of 38,641 men and 93,661 women who were free of PD at baseline, Gao et al. (2009) found an association between decreasing darkness of natural hair color in early adulthood and increased PD risk. The pooled relative risks (RR) for PD were 1.0 (reference risk), 1.40, 1.61, and 1.93 for black, brown, blond, and red hair, respectively. These results were significant after adjusting for age, smoking, ethnicity, and other covariates. The associations between hair color and PD were particularly strong for onset before age 70 years. In a case-control study of 272 PD cases and 1,185 controls, there was an association between the cys151 SNP of the MC1R gene (R151C; 155555.0004), which confers red hair, and increased risk of PD relative to the arg151 SNP (relative risk of 3.15 for the cys/cys genotype). Noting that melanin, like dopamine, is synthesized from tyrosine, and that PD is characterized by the loss of neuromelanin-containing neurons in the substantia nigra, Gao et al. (2009) postulated a link between pigmentation and development of PD. Herrero Hernandez (2009) independently noted the association. Dong et al. (2014) did not find a significant association between the R151C MC1R variant and Parkinson disease in 2 large datasets of 808 PD patients and 1,623 controls and 5,333 PD patients and 12,019 controls. All the participants were non-Hispanic whites. Tell-Marti et al. (2015) did not find a significant association between the R151C MC1R variant and Parkinson disease among 870 Spanish PD patients and 736 controls.
In a study of 157,036 individuals, who did not have PD at baseline, over a 14- to 20-year follow-up period, Gao et al. (2009) identified 616 incident PD cases. A family history of melanoma in a first-degree relative was associated with a higher risk of PD (RR, 1.85; p = 0.004) after adjusting for smoking, ethnicity, caffeine intake, and other covariates. There was no association between a family history of colorectal, lung, prostate, or breast cancer and PD risk. The findings supported the notion that melanoma and Parkinson disease share common genetic components.
Shahnawaz et al. (2020) showed that the alpha-synuclein (SNCA; 163890)-protein misfolding cyclic amplification (PMCA) assay can discriminate between samples of cerebrospinal fluid from patients diagnosed with Parkinson disease and samples from patients with multiple system atrophy (MSA1; 146500), with an overall sensitivity of 95.4%. Shahnawaz et al. (2020) used a combination of biochemical, biophysical, and biologic methods to analyze the product of alpha-synuclein-PMCA, and found that the characteristics of the alpha-synuclein aggregates in the cerebrospinal fluid could be used to readily distinguish between Parkinson disease and multiple system atrophy. They also found that the properties of aggregates that were amplified from the cerebrospinal fluid were similar to those of aggregates that were amplified from the brain. These findings suggested that alpha-synuclein aggregates that are associated with Parkinson disease and multiple system atrophy corresponded to different conformational strains of alpha-synuclein, which can be amplified and detected by alpha-synuclein-PMCA.
There has been much controversy regarding the genetics of Parkinson disease, as no specific pattern of inheritance is readily apparent, and reports of Parkinson disease and parkinsonism may not necessarily refer to the same disease entity (Nussbaum and Polymeropoulos, 1997). However, a familial component to Parkinson disease and parkinsonism has long been recognized.
Gowers (1900) is believed to have been the first to observe that patients with PD often had an affected relative, and he suggested that hereditary factors may be important. Bell and Clark (1926) reviewed published pedigrees of 'paralysis agitans' and reported an additional one. Allan (1937) described impressive pedigrees from North Carolina.
Twin Studies
Kissel and Andre (1976) described a pair of female MZ twins, both of whom had a combination of parkinsonism and anosmia. Olfactory impairment is frequent in PD (Ward et al., 1983). Both twins reported onset of symptoms at age 36 years, which is unusually early, particularly for women (Kessler, 1978). Kissel and Andre (1976) noted that 2 families with the same association had previously been reported and they suggested a causative role for a genetically determined anomaly of dopamine metabolism.
Duvoisin et al. (1981) found zero concordance for Parkinson disease in the first 12 monozygotic twin pairs examined in an on-going twin study. There was evidence of premorbid personality differences between probands and cotwins dating back to late adolescence or early adult years. Among 43 monozygotic and 19 dizygotic twin pairs, Ward et al. (1983) found that only 1 monozygotic twin pair was definitely concordant for PD. Ward et al. (1983) noted that concordance for PD is no more frequent in twins than would be expected from the incidence of the disease, and concluded that major factors in the etiology of PD must be nongenetic.
Mendelian Inheritance
Spellman (1962) described a family in which multiple members in 4 generations had parkinsonism beginning in their thirties and progressing rapidly to death in 2 to 12 years. Tune et al. (1982) described Parkinson disease in 4 persons in 3 generations. Several of these also had manic-depressive illness.
Barbeau and Pourcher (1982, 1983) suggested that mendelian inheritance obtains in some cases, particularly in those whose illness started before the age of 40. In this early-onset group, there was a 46% incidence of familial cases. They divided Parkinson disease into 4 etiologic categories: postencephalitic, idiopathic, genetic, and symptomatic. They proposed the existence of 2 genetic subtypes: an akineto-rigid subtype transmitted as an autosomal recessive and a subtype with prominent tremor, dominant inheritance, and a high prevalence of family members with essential tremor.
Lazzarini et al. (1994) found that the cumulative risk of PD among sibs of probands with affected parents was increased significantly over that for sibs of probands without affected parents, suggesting significant familial aggregation in a subset of randomly ascertained families. Furthermore, in 80 multicase families, age-adjusted ratios approaching 0.5 and similar proportions of affected parents and sibs, as well as the distribution of ancestral secondary cases, were compatible with an autosomal dominant mode of inheritance with reduced penetrance in a subset of PD. Payami et al. (1995) studied age of onset of 137 patients with idiopathic Parkinson disease. The 21 probands with an affected parent, aunt, or uncle were younger at onset of PD (47.7 +/- 8.8 years) than were the 11 probands with an affected sib only (60.3 +/- 12.9 years) and the 105 probands with no affected relatives (59.2 +/- 11.4 years). Age of onset of affected family members differed significantly between generations (p = 0.0001) and was earlier, by an average of 17 years, in the proband generation than in the parental generation. The data were consistent with genetic anticipation and suggested the involvement of an unstable trinucleotide repeat. Markopoulou et al. (1995) studied a Greek-American kindred with 98 individuals in 6 generations. Sixteen individuals in 3 generations developed parkinsonism, which appeared to be transmitted in an autosomal dominant manner with evidence of anticipation. No pathologic data were presented.
Plante-Bordeneuve et al. (1995) studied 14 families in which the proband and at least one relative were affected by clinically typical Parkinson disease, based on Parkinson Disease Society brain bank diagnostic criteria (Hughes et al., 1992). No clinical differences were found between 31 individuals with familial Parkinson disease and 31 age-matched sporadic Parkinson disease controls. In the 14 families, genetic transmission was compatible with autosomal dominant transmission with several cases of male-to-male transmission. Although the total segregation ratio was 0.25, this was age-dependent, with a penetrance of zero below age 30 and a penetrance of 0.43 over the age of 70. Age at onset was identical within a generation but it was 26 +/- 4.6 years earlier in children than parents of the 8 multigenerational kindreds studied, suggesting an anticipation phenomenon.
Bonifati et al. (1995) used epidemiologic methods to determine the frequency of clinical features of familial Parkinson disease. By studying 100 consecutive Parkinson disease cases presenting to their clinic, family history for Parkinson disease was positive in 24% of Parkinson disease cases and in only 6% of spouse controls. In a larger study of 22 nonconsecutive Parkinson disease families with at least 2 living and personally examined cases, the crude segregation ratios were similar for parents and sibs, with lifetime cumulative risks approaching 0.4. These data supported autosomal dominant inheritance with a strong age factor in penetrance.
Nussbaum and Polymeropoulos (1997) reviewed the genetics of Parkinson disease. They stated that for the previous 40 years, research into Parkinson disease had predominantly been the province of epidemiologists interested in pursuing the connection between the disorder and environmental factors such as viral infection or neurotoxins. Hereditary influences were discounted because of a high discordance rate among monozygotic twins found in studies that were later shown to be inadequate and inconclusive. On the other hand, a positive family history was recognized as a major risk factor for the disease and it became increasingly apparent from neuropathologic studies that the common, idiopathic form of Parkinson disease had a specific pathologic correlate in the form of Lewy bodies, an eosinophilic cytoplasmic inclusion body, distributed diffusely throughout the substantia nigra, hypothalamus, hippocampus, autonomic ganglia, and olfactory tracts. They referred to the 'particularly prescient paper' of Sommer and Rocca (1996), in which the authors suggested that autosomal dominant PD may be caused by a missense mutation in a cellular protein that changes its physical-chemical properties, leading to accumulation of the abnormal protein and neuronal death. This hypothesis has received substantial support.
Maher et al. (2002) collected information involving the nuclear families of 948 consecutively ascertained Parkinson disease index cases from 3 U.S. medical centers. They performed segregation analysis to assess evidence for the presence of a mendelian pattern of familial transmission. The proportion of male (60.4%) and female (39.6%) cases, the mean age of onset (57.7 years), and the proportion of affected fathers (4.7%), mothers (6.6%), brothers (2.9%), and sisters (3.2%) were similar across the 3 institutions. They concluded that the analyses supported the presence of a rare major mendelian gene for PD in both the age-of-onset and susceptibility model. The age-of-onset model provided evidence for a gene that influences age-dependent penetrance of PD, influencing age of onset rather than susceptibility. Maher et al. (2002) also found evidence for a mendelian gene influencing susceptibility to the disease. It was not evident whether these 2 analyses were modeling the same gene or different genes with different effects on PD. Genes influencing penetrance may interact with environmental factors or other genes to increase the risk of PD. Such gene-environment interactions, involving reduced penetrance in PD, may explain the low concordance rates among monozygotic twins for this disorder.
In a comparison of 221 PD patients with age at onset of 50 years or younger, 266 PD patients with age at onset of 50 years or greater, and 409 unaffected controls, Marder et al. (2003) found a similar relative risk (RR) of PD among first-degree relatives of both the early- and late-onset groups (RR = 2.9 and 2.7, respectively) compared to those of controls. There was also an increased risk of PD in sibs of affected patients (RR = 7.9 for early-onset and 3.6 for late-onset) compared to those of controls. Parents of the early-onset group were not at a significantly increased risk compared to those of controls (RR = 1.7), and parents of the late-onset group were at a higher increased risk compared to those of controls (RR = 2.5). Marder et al. (2003) concluded that the pattern was consistent with an autosomal recessive contribution to the inheritance of early- but not late-onset PD, but also noted that genetic factors are important in both groups.
'Familial Component'
Zareparsi et al. (1998) performed complex segregation analyses using kindreds of 136 Parkinson disease patients randomly ascertained from a clinic population. They rejected the hypotheses of a nontransmissible environmental factor, a major gene or type (sporadic), and all mendelian inheritance (dominant, recessive, additive, decreasing). They concluded that familial clustering of PD in this dataset was best explained by a 'rare familial factor' which is transmitted in a nonmendelian fashion and influences the age at onset of PD.
Montgomery et al. (1999) used a previously reported PD test battery to check for mild signs of motor slowing, impaired sense of smell, and depressed mood in first-degree relatives of patients with Parkinson disease, most of whom were considered sporadic cases. Abnormalities on the test battery were found in 22.5% of first-degree relatives, all of whom were judged normal on standard neurologic examination, but in only 9% of age-matched controls. The authors interpreted this familial clustering of minimal parkinsonian tendencies as an indication of genetic predisposition to Parkinson disease even in sporadic cases.
Sveinbjornsdottir et al. (2000) reviewed the medical records and confirmed the diagnosis of Parkinson disease in 772 living and deceased patients in whom the diagnosis had been made in Iceland during the previous 50 years. With the use of an extensive computerized database containing genealogic information on 610,920 people in Iceland over the past 11 centuries, they conducted several analyses to determine whether the patients were more related to each other than random members of the population. They found that there was a genetic component to Parkinson disease, including a subgroup of 560 patients with late-onset disease (onset after 50 years of age): patients with Parkinson disease were significantly more related to each other than were subjects in matched groups of controls, and this relatedness extended beyond the nuclear family. There was no highly penetrant mendelian pattern of inheritance, and both early and late-onset forms often skipped generations. The risk ratio for Parkinson disease was 6.7 for sibs, 3.2 for offspring, and 2.7 for nephews and nieces of patients with late-onset Parkinson disease.
Racette et al. (2002) described a very large Amish pedigree with classic idiopathic Parkinson disease in multiple members. They examined 113 members and classified 67 as having no evidence of PD, 17 as clinically definite PD, 6 as clinically probable PD, and 23 as clinically possible PD. The mean age at onset of the clinically definite subjects was 56.7 years. The mean kinship coefficient in the subjects with PD and those with PD by history was higher (p = 0.007) than in a group of age-matched normal Amish control subjects, providing evidence that PD is inherited in this family. Sequence analysis did not reveal any mutations in known PD genes. No single haplotype cosegregated with the disease in any of the chromosomal regions previously found to be linked to PD.
Environmental Factors
Some findings suggest that environmental factors may be more important than genetic factors in familial aggregation of Parkinson disease. Calne et al. (1987) reported 6 families in which onset of symptoms tended to occur at approximately the same time regardless of the age of the patient. In a hospital-based survey, Teravainen et al. (1986) concluded that there is a trend toward lower age of onset of Parkinson disease.
Calne and Langston (1983) advanced the view that in most cases the cause is an environmental factor, possibly toxic, superimposed on a background of slow, sustained neuronal loss due to advancing age. Finding parkinsonism in 1-methyl-4-phenyl-1,2,3,6-tetrahydropteridine (meperidine; MPTP) drug users (Langston et al., 1983) revived interest in reexamining environmental factors. Barbeau et al. (1985) also postulated that Parkinson disease is the result of environmental factors acting on genetically susceptible persons against a background of 'normal' aging.
Nathans (2005) noted the remarkable coincidence that the abbreviation MPTP, for the drug that causes Parkinson disease by selectively damaging dopaminergic neurons, is coincidentally the code for the first 4 amino acids of human, mouse, and rat tyrosine hydroxylase, the enzyme which marks all dopaminergic neurons.
In a case-control study of 418 Chinese PD patients and 468 controls, Tan et al. (2007) found a significant association between caffeine intake and decreased risk of PD (p = 2.01 x 10(-5)). The odds ratio was 0.48 for moderate and high caffeine intake and 0.71 for low intake. No difference was observed with genotyping for a common SNP in the CYP1A2 gene (124060), which influences the level of caffeine metabolism. The findings suggested that caffeine and its main metabolite paraxanthine are both neuroprotective.
Multifactorial Inheritance
Analysis of the experience at the Mayo Clinic led Kondo et al. (1973) to conclude that irregular dominant transmission is untenable and that multifactorial inheritance with heritability of about 80% is more likely. Young et al. (1977) favored multifactorial inheritance but could not exclude autosomal dominance with reduced penetrance, especially for some families. Affected relatives were bilaterally distributed more often than would be expected for autosomal dominance.
Vaughan et al. (2001) reviewed the genetics of parkinsonism. They suggested that nigral degeneration with Lewy body formation and the resulting clinical picture of Parkinson disease may represent a final common pathway of a multifactorial disease process in which both environmental and genetic factors have a role.
Also see review of Parkinson disease by Nussbaum and Ellis (2003).
Mitochondrial Inheritance
Another theory of parkinsonism suggests that genetic predisposition may be transmitted through mitochondrial inheritance (Di Monte, 1991); see 556500. Schapira (1995) reviewed nuclear and mitochondrial genetics in Parkinson disease. He stated that Gowers (1900) had noted the occurrence of PD in relatives and suggested that hereditary factors are important.
From a study of Parkinson disease in twins, Tanner et al. (1999) concluded that 'no genetic component was evident when the disease begins after age 50 years.' Parker et al. (1999) and Simon (1999) pointed out that whereas this may be true as far as mendelian (nuclear) genetic mechanisms are concerned, this may not be true for mitochondrial factors in Parkinson disease. Since MZ and DZ twins each receive all of their mitochondrial DNA from their mother, differences in concordance rates between MZ and DZ twins cannot be used to address the potential influence of mitochondrial genetic factors.
To test the hypothesis that mitochondrial variation contributes to Parkinson disease expression, van der Walt et al. (2003) genotyped 10 single-nucleotide polymorphisms that define the European mitochondrial DNA haplogroups in 609 white patients with Parkinson disease and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J (odds ratio = 0.55; 95% CI 0.34-0.91; p = 0.02) or K (odds ratio = 0.52; 95% CI 0.30-0.90; p = 0.02) demonstrated a significant decrease in risk of Parkinson disease versus individuals carrying the most common haplogroup H. Furthermore, a specific SNP that defines these 2 haplogroups, 10398G (516002.0002), is strongly associated with this protective effect (odds ratio = 0.53; 95% CI 0.39-0.73; p = 0.0001). The 10398G SNP causes a nonconservative amino acid change from threonine to alanine within the ND3 (516002) of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men. In addition, the 9055A SNP of ATP6 (516060) demonstrated a protective effect for women. Van der Walt et al. (2003) concluded that ND3 is an important factor in Parkinson disease susceptibility among white individuals and could help explain the role of complex I in Parkinson disease expression.
Gill et al. (2003) delivered glial cell line-derived neurotrophic factor (GDNF; 600837) directly into the putamen of 5 Parkinson patients in a phase 1 safety trial. One catheter needed to be repositioned and there were changes in the MRIs that disappeared after lowering the concentration of GDNF. After 1 year, there were no serious clinical side effects, a 39% improvement in the off-medication motor subscore of the Unified Parkinson Disease Rating Scale (UPDRS), and a 61% improvement in the activities of daily living subscore. Medication-induced dyskinesias were reduced by 64% and were not observed off medication during chronic GDNF delivery. Positron emission tomography (PET) scans of [18F]dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, suggesting a direct effect of GDNF on dopamine function.
Voon et al. (2007) evaluated 21 patients with Parkinson disease who developed pathologic gambling (606349) after receiving pharmacologic treatment with dopaminergic agonists. Compared to 42 PD patients without compulsive behaviors, those who developed pathologic gambling had a younger age at PD onset, higher novelty seeking (601696), tended to have medication-induced hypomania or mania, impaired planning, and a personal or family history of alcohol use disorders (103780).
L-DOPA is predominantly metabolized to the inactive 3-O-methyldopa by COMT (116790). Entacapone is a COMT inhibitor that acts to prolong the half-life of L-DOPA and yields prolonged therapeutic benefits. A val158-to-met (V158M) polymorphism in the COMT gene (rs4680; 116790.0001) confers increased (val) or decreased (met) COMT activity. In a randomized control trial of 33 PD patients, Corvol et al. (2011) found that those homozygous for the high-activity val158 allele had significantly increased COMT inhibition by entacapone and significantly better bioavailability of and clinical response to L-DOPA compared to patients homozygous for the low-activity met158 allele. The findings indicated that homozygosity for the val158 allele in PD patients enhances the effect of entacapone on the pharmacodynamics and pharmacokinetics of levodopa. The response to entacapone in heterozygous patients was not studied.
Using unbiased phenotypic screens as an alternative to target-based approaches, Tardiff et al. (2013) discovered an N-aryl benzimidazole (NAB) that strongly and selectively protected diverse cell types from alpha-synuclein (163890) toxicity. Three chemical genetic screens in wildtype yeast cells established that NAB promoted endosomal transport events dependent on the E3 ubiquitin ligase Rsp5 (NEDD4; 602278). These same steps were perturbed by alpha-synuclein itself. Tardiff et al. (2013) concluded that NAB identifies a druggable node in the biology of alpha-synuclein that can correct multiple aspects of its underlying pathology, including dysfunctional endosomal and endoplasmic reticulum-to-Golgi-vesicle trafficking.
Chung et al. (2013) exploited mutation correction of iPS cells and conserved proteotoxic mechanisms from yeast to humans to discover and reverse phenotypic responses to alpha-synuclein, a key protein involved in Parkinson disease. Chung et al. (2013) generated cortical neurons from iPS cells of patients harboring alpha-synuclein mutations (A53T; 163890.0001), who are at high risk of developing PD dementia. Genetic modifiers from unbiased screens in a yeast model of alpha-synuclein toxicity led to identification of early pathogenic phenotypes in patient neurons, including nitrosative stress, accumulation of endoplasmic reticulum-associated degradation substrates, and ER stress. A small molecule, NAB2, identified in a yeast screen, and NEDD4, the ubiquitin ligase that it affects, reversed pathologic phenotypes in these neurons.
Evidence for Genetic Heterogeneity
Polymeropoulos et al. (1996) demonstrated genetic linkage between an autosomal dominant form of PD and genetic markers on 4q21-q23. The locus was designated PARK1 (168601). In 94 Caucasian families, Scott et al. (1997) could not demonstrate linkage to 4q21-q23. They also found no linkage even when the 22 families from their study with at least 1 case of early-onset PD were examined separately. Gasser et al. (1997) excluded linkage in 13 multigenerational families with Parkinson disease, with the exception of 1 family for which they achieved a maximum multipoint lod score of 1.5 for genetic markers in the 4q21-q23 region.
Scott et al. (2001) described a genetic linkage study conducted in 1995-2000 in which a complete genomic screen was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. Significant evidence for linkage was found in 5 distinct chromosomal regions: chromosome 6 in the parkin gene (PARK2; 602544) in families with at least 1 individual with PD onset at younger than 40 years (lod = 5.47); chromosomes 17q (lod = 2.62), 8p (lod = 2.22), and 5q (lod = 1.50) overall and in families with late-onset PD; and 9q (lod = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients. The data suggested that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic, late-onset PD.
Pankratz et al. (2002) studied 160 multiplex families with PD in which there was no evidence of mutations in the parkin gene, and used multipoint nonparametric linkage analysis to identify PD susceptibility genes. For those individuals with a more stringent diagnosis of verified PD, the highest lod scores were observed on the X chromosome and on chromosome 2 (lod scores equal to 2.1 and 1.9, respectively). Analyses performed with all available sib pairs, i.e., all examined individuals treated as affected regardless of their final diagnostic classification, yielded even greater evidence of linkage to the X chromosome and to chromosome 2 (lod scores equal to 2.7 and 2.5, respectively). Evidence of linkage was also found to chromosomes 4, 5, and 13 (lod scores greater than 1.5). Pankratz et al. (2002) considered their findings consistent with those of other linkage studies that had reported linkage to chromosomes X and 5.
Pankratz et al. (2003) studied 754 affected individuals, comprising 425 sib pairs, to identify PD susceptibility genes. Genomewide, nonparametric linkage analyses revealed potential loci on chromosomes 2, X, 10, and 14. The authors hypothesized that gene-by-gene interactions are important in PD susceptibility.
Associations Pending Confirmation
Maraganore et al. (2005) performed a 2-tiered, genomewide association study of PD including 443 sib pairs discordant for PD and 332 case-unrelated control pairs. A SNP (rs7702187) within the semaphorin-5A gene (SEMA5A; 609297) on chromosome 5p had the lowest combined p value (p = 7.62 x 10(-6)). The protein encoded by this gene plays an important role in neurogenesis and in neuronal apoptosis, which was consistent with hypotheses regarding PD pathogenesis.
Gao et al. (2009) conducted a genomewide linkage screen of 5,824 SNPs in 278 families of European non-Hispanic descent to localize regions that harbor susceptibility loci for Parkinson disease. These 278 families included 158 families included in a previous screen (Scott et al., 2001) and 120 families not previously screened. In the overall screen of all 278 families, the highest multipoint MLOD scores were obtained under a dominant model of inheritance in an 11-cM interval on chromosome 3q25 (MLOD = 2.0) and a 9-cM interval on chromosome 18q11 (MLOD = 1.8). Since the combined screen did not detect linkage overall in regions previously implicated, Gao et al. (2009) suspected that clinical and locus heterogeneity might exist. They stratified the dataset into previously screened and unscreened families. In the 120 families not previously screened, Gao et al. (2009) achieved significant evidence for linkage on chromosome 18q11 (maximum lod score = 4.1) and suggestive evidence on chromosome 3q25 (maximum lod score = 2.5). There was little evidence for linkage to these regions overall in the original 158 families. Simulation studies suggested that these findings were likely due to locus heterogeneity rather than random statistical error. See also PARK18 (614251), which is caused by mutation in the EIF4G1 gene (600495) on 3q27.
To identify susceptibility variants for Parkinson disease, Satake et al. (2009) performed a genomewide association study and 2 replication studies in a total of 2,011 cases and 18,381 controls from Japan. They identified a novel susceptibility locus on chromosome 4p15. Four SNPs (rs11931532, rs12645693, rs4698412, and rs4538475) reached p less than 5 x 10(-7) in the combined analysis. The 4 SNPs were located 4.1 kb downstream of intron 8 of the BST1 gene (600387). Satake et al. (2009) also identified a locus on chromosome 1q32 (PARK16; 613164), replicated by Simon-Sanchez et al. (2009), and replicated associations on 4q22 (see PARK1, 168601) and 12q12 (see PARK8, 607060). Tan et al. (2010) confirmed associations at the PARK16, PARK1, and PARK8 loci in 433 PD patients and 916 controls, all of Chinese ethnicity. However, they did not identify a significant association at the BST1 locus.
By a genomewide association study of 2,000 individuals with late-onset PD and 1,986 unaffected controls, all of European ancestry from the NeuroGenetics Research Consortium (NGRC), Hamza et al. (2010) found an association between PD and rs11248051 in the GAK gene (602052) on chromosome 4p (p = 3.1 x 10(-4); odds ratio (OR) of 1.32). When combined with data from a previous study (Pankratz et al., 2009), metaanalysis of the combined dataset of 2,843 patients yielded a significant association (p = 3.2 x 10(-9); OR, 1.46). Hamza et al. (2010) designated this possible locus PARK17, but that symbol has been used for a confirmed PD locus on chromosome 16q13 (see 614203). They also found a significant association between PD and rs3129882 in intron 1 of the HLA-DRA (142860) gene on chromosome 6p21.3 (p = 2.9 x 10(-8)). The authors designated this possible locus PARK18, but that symbol has been used for a confirmed PD locus on chromosome 3q27 (see 614251). The association was significant even after adjusting for age, sex, and genetic substructure among Americans of European descent (as defined by Jewish ancestry and country of origin). The findings were replicated in 2 datasets comprising 1,447 patients, and metaanalysis of the 3 populations showed a combined p value of 1.9 x 10(-10) and odds ratio of 1.26. The HLA association was uniform across all genetic and environmental risk strata, and was strong in both sporadic (p = 5.5 x 10(-10)) and late-onset (p = 2.4 x (10-8)) disease. A data repository of expression QTL indicated that rs3129882 is a cis-acting regulatory variant that correlated significantly with expression levels of HLA-DRA, HLA-DQA2 (613503), and HLA-DRB5 (604776). Hamza et al. (2010) suggested that their findings supported the involvement of the immune system in the pathogenesis of Parkinson disease. However, Mata et al. (2011) failed to replicate the associations between Parkinson disease and the loci at chromosome 4p and 6p21 in a study of 1,445 PD patients and 1,161 controls from northern Spain. The SNPs studied included rs11248051 in the GAK gene and rs3129882 in the HLA-DRA gene. Mata et al. (2011) concluded that the loci designated PARK17 and PARK18 by Hamza et al. (2010) required further validation.
Polymeropoulos (1997) noted that Polymeropoulos et al. (1997) had reported a total of 4 families in which mutation in the alpha-synuclein gene (SNCA; 163890) could be shown to be responsible for early-onset Parkinson disease (PARK1; 168601). However, mutation was not detected in 50 individuals with sporadic Parkinson disease or in 2 other families with late onset of the illness.
Theuns et al. (2006) pointed out that it is widely accepted that genetic causes of susceptibility to complex diseases reflect a different spectrum of sequence variants than mutations that dominate monogenic disorders. This spectrum includes mutations that alter gene expression; in particular, promoter mutations have been shown to result in inherited diseases, including neurodegenerative brain diseases. They pointed to the fact that in Parkinson disease, 2 variants in the 5-prime regulatory region of NR4A2 (601828.0001 and 601828.0002) were found to be associated with familial PD and markedly reduced NR4A2 mRNA levels. Also, multiple association studies showed that variations in the 5-prime regulatory regions of SNCA (163890) and PARK2 (602544) increase PD susceptibility, with some variations increasing disease risk by modulating gene transcription. In Alzheimer disease (104300), promoter mutations in PSEN1 (104311) can explain the increased risk for early-onset AD by decreasing expression levels of PSEN1 in neurons.
Considering 4 putative PD risk regions, SNCA, MAPT, GAK, and HLA-DRA in 2,000 late-onset PD patients and 1,986 unaffected controls from the NGRC population, Hamza et al. (2010) found that the risk of Parkinson disease was doubled for individuals who had 4 risk alleles (OR of 2.49, p = 6.5 x 10(-8)), and was increased 5-fold for individuals who had 6 or more risk alleles (OR of 4.95, p = 5.5 x 10(-13)). These findings supported the notion that Parkinson disease risk is due to cumulative effects of risk factors that each have a modest individual effect.
Association with the MAPT gene
The demonstration of linkage of idiopathic Parkinson disease to 17q21 (Scott et al., 2001) made the tau gene (MAPT; 157140) a good candidate as a susceptibility gene for idiopathic PD. Martin et al. (2001) tested 5 single-nucleotide polymorphisms (SNPs) within the MAPT gene for association with PD in a sample of 1,056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center. They used family-based tests of association. The sample consisted of 426 affected and 579 unaffected family members; 51 individuals had unclear PD status. Both individual SNPs and SNP haplotypes in the MAPT gene were analyzed. Significant evidence of association was found for 3 of the 5 SNPs tested. Strong evidence of association was found with haplotype analysis, with a positive association with 1 haplotype (p = 0.009) and a negative association with another haplotype (p = 0.007). Substantial linkage disequilibrium (p less than 0.001) was detected between 4 of the 5 SNPs. The study was interpreted as implicating MAPT as a susceptibility gene for idiopathic Parkinson disease.
Association with the Glucocerebrosidase (GBA) Gene
An association has been reported between parkinsonism and type I Gaucher disease (230800) (Neudorfer et al., 1996; Tayebi et al., 2001; Bembi et al., 2003), the most prevalent, recessively inherited disorder of glycolipid storage. Simultaneous occurrence of Parkinson disease and Gaucher disease is marked by atypical parkinsonism generally presenting by the fourth through sixth decades of life. The combination progresses inexorably and is refractory to conventional anti-Parkinson therapy (Varkonyi et al., 2003).
Aharon-Peretz et al. (2004) studied the association of Parkinson disease with Gaucher disease, which is caused by mutation in the GBA gene (606463), which encodes the lysosomal enzyme glucocerebrosidase. They screened 99 Ashkenazi patients with idiopathic Parkinson disease, 74 Ashkenazi patients with Alzheimer disease, and 1,543 healthy Ashkenazi Jews for the 6 GBA mutations that are most common among Ashkenazi Jews. One or 2 mutant GBA alleles were found in 31 patients with Parkinson disease (31.3%): 28 were heterozygous and 3 were homozygous for one of these mutations. Among the 74 patients with Alzheimer disease, 3 (4.1%) were carriers of Gaucher disease. Among the 1,543 controls, 95 (6.2%) were carriers of Gaucher disease. Patients with Parkinson disease had significantly greater odds of being carriers of Gaucher disease than did patients with Alzheimer disease (OR = 10.8) or controls (OR = 7.0). Among the patients with Parkinson disease, those who were carriers of Gaucher disease were younger than those who were not carriers (mean age at onset, 60.0 years vs 64.2 years, respectively). Aharon-Peretz et al. (2004) suggested that some GBA mutations are susceptibility factors for Parkinson disease.
Toft et al. (2006) did not find an association between PD and 2 common GBA mutations (L444P; 606463.0001 and N370S; 606463.0003) among 311 Norwegian patients with Parkinson disease. Mutant GBA alleles were identified in 7 (2.3%) patients and 8 (1.7%) controls.
Tan et al. (2007) identified a heterozygous GBA L444P mutation in 8 (2.4%) of 331 Chinese patients with typical Parkinson disease and none of 347 controls. The age at onset was lower and the percentage of women higher in patients with the L444P mutation compared to those without the mutation. Tan et al. (2007) noted that the findings were significant because Gaucher disease is extremely rare among the Chinese.
Gan-Or et al. (2008) found that 75 (17.9%) of 420 Ashkenazi Jewish patients with PD carried a GBA mutation, compared to 4.2% of elderly and 6.35% of young controls. The proportion of severe GBA mutation carriers among patients was 29% compared to 7% among young controls. Severe and mild GBA mutations increased the risk of developing PD by 13.6- and 2.2-fold, and were associated with decreased age at PD onset. Gan-Or et al. (2008) concluded that genetic variance in the GBA gene is a risk factor for PD.
Gutti et al. (2008) identified the GBA L444P mutation in 4 (2.2%) of 184 Taiwanese patients with PD. Six other GBA variants were identified in 1 patient each, yielding a total of 7 different mutations in 10 patients (5.4%). Gutti et al. (2008) suggested that sequencing the entire GBA gene would reveal additional variants that may contribute to PD.
Mata et al. (2008) identified heterozygosity for either the GBA L444P or N370S mutation in 21 (2.9%) of 721 PD patients, 2 (3.5%) of 57 patients with Lewy body dementia, and 2 (0.4%) of 554 control subjects individuals, all of European origin. Mata et al. (2008) estimated that the population-attributable risk for GBA mutations in Lewy body disorders was only about 3% in patients of European ancestry.
In a 16-center worldwide study comprising 5,691 PD patients (including 780 Ashkenazi Jewish patients) and 4,898 controls (387 Ashkenazis), Sidransky et al. (2009) demonstrated a strong association between GBA mutations and Parkinson disease. Direct sequencing for only the L444P or N370S mutations identified either mutation in 15% of Ashkenazi patients and 3% of Ashkenazi controls. Among non-Ashkenazi individuals, either mutation was found in 3% of patients and less than 1% of controls. However, full gene sequencing identified GBA mutations in 7% of non-Ashkenazi patients. The odds ratio for any GBA mutation in patients compared to controls was 5.43 across all centers. Compared to PD patients without GBA mutations, patients with GBA mutations presented earlier with the disease, were more likely to have affected relatives, and were more more likely to have atypical manifestations, including cognitive defects. Sidransky et al. (2009) concluded that while GBA mutations are not likely a mendelian cause of PD, they do represent a susceptibility factor for development of the disorder.
Neumann et al. (2009) identified 14 different heterozygous mutations in the GBA gene, in 33 (4.18%) of 790 British patients with Parkinson disease and in 3 (1.17%) of 257 controls. Three novel mutations (see, e.g., D443N; 606463.0048) were identified, and most common mutations were L444P (in 11 patients), N370S (in 8 patients), and R463C (in 3 patients; 606463.0008). Four (12%) patients had a family history of the disorder, whereas 29 (88%) had sporadic disease. The mean age at onset was 52.7 years, and 12 (39%) patients had onset before age 50. Fifteen (about 50%) patients with GBA mutations developed cognitive decline, including visual hallucinations. The male to female ratio of GBA carriers within the PD group was 5:2, which was significantly higher than that of the whole study group. Most patients responded initially to L-DOPA treatment. Neuropathologic examination of 17 GBA mutation carriers showed typical PD changes, with widespread and abundant alpha-synuclein pathology, and most also had neocortical Lewy body pathology. The prevalence of GBA mutations in British patients with sporadic PD was 3.7%, indicating that mutations in the GBA gene may be the most common risk factor for development of PD in this population. In an accompanying letter, Gan-Or et al. (2009) found that the data presented by Neumann et al. (2009) indicated that patients with mild GBA mutations had a later age at onset (62.9 years vs 49.8 years) and lower frequency of cognitive symptoms (25% vs 55.6%) compared to patients with severe GBA mutations.
Alcalay et al. (2010) identified mutations in the GBA gene in 64 (6.7%) of 953 patients with early-onset PD before age 51, including 77 and 139 individuals of Hispanic and Jewish ancestry, respectively. There were 18 heterozygous L444P carriers, 38 heterozygous N370S carriers, and 2 homozygous N370S carriers. Six of the 64 patients had a GBA mutation and another mutation in the LRRK2 or PRKN (PARK2; 602544) genes.
Reclassified Variants
The R621C variant in the SNCAIP gene (603779.0001) as a cause of Parkinson disease has been reclassified as a variant of unknown significance. In 2 apparently sporadic patients with Parkinson disease, Marx et al. (2003) found an arg621-to-cys (R621C) mutation in synphilin-1 (603779.0001).
The S445A variant in the GLUD2 gene (300144.0001) that was identified as a modifier for Parkinson disease has been reclassified as a polymorphism. Plaitakis et al. (2010) identified a c.1492T-G polymorphism in the GLUD2 gene (S445A; 300144.0001) that was associated with earlier age of onset in 2 cohorts of patients with Parkinson disease.
Associations Pending Confirmation
---Association with CYP2D4
Investigating the postulate that PD may have an environmental cause, Barbeau et al. (1985) noted that many potential neurotoxic xenobiotics are detoxified by hepatic cytochrome P450. They studied one such system in 40 patients with Parkinson disease and 40 controls, and found that significantly more patients than controls had partially or totally defective 4-hydroxylation of debrisoquine (608902). Poor metabolizers had earlier onset of disease. See 124030.
Bordet et al. (1994) investigated a genetic polymorphism of the cytochrome P450 CYP2D6 gene (124030) in 105 patients with idiopathic Parkinson disease and 15 patients with diffuse Lewy body disease. They found no relationship between the CYP2D6 gene associated with poor metabolism of debrisoquine with either idiopathic Parkinson disease or diffuse Lewy body disease. Sandy et al. (1996) found no significant differences in CYP2D6 allelic frequencies between early-onset Parkinson disease cases (51 years of age or less) and controls.
---Association with MAOB and/or COMT
Kurth et al. (1993) found a single-strand conformation polymorphism in intron 13 of the monoamine oxidase B gene (309860) and found a significantly higher frequency of 1 allele in their parkinsonian population compared with the control group. Ho et al. (1995), however, were unable to substantiate this claim.
Wu et al. (2001) analyzed 224 Taiwanese patients with PD for MAOB intron 13 G (309860) and COMT L (V158M; 116790.0001) polymorphisms and found that the MAOB G genotype (G in men, G/G in women) was associated with a 2.07-fold increased relative risk for PD, an association which was stronger for men than for women. Although COMT polymorphism alone was not associated with an increased risk for PD, when it was considered in conjunction with the MAOB G genotype, there was a 2.4-fold increased relative risk for PD. In men, the combined alleles, MAOB G and COMT L, increased the relative risk for PD to 7.24. Wu et al. (2001) suggested that, in Taiwanese, the development of PD may be related to the interaction of 2 or more genes involved in dopamine metabolism.
---Association with GSK3B
Kwok et al. (2005) identified 2 functional SNPs in the GSK3B (605004) gene that influenced GSK3B transcriptional activity and correlated with enhanced phosphorylation of MAPT in vitro, respectively. Conditional logistic regression analysis of the genotypes of 302 Caucasian PD patients and 184 Chinese PD patients found an association between the GSK3B polymorphisms, MAPT haplotype, and risk of PD. Kwok et al. (2005) concluded that GSK3B polymorphisms interact with MAPT haplotypes to modify disease risk in PD.
---Association with IL1B
Among 52 Finnish patients with PD, Mattila et al. (2002) found an increased frequency of the interleukin 1-beta gene (IL1B; 147720) -511 polymorphism compared to controls (allele frequency of 0.96 in PD and 0.73 in controls; p = 0.001). The calculated relative risk of PD for patients carrying at least one IL1B allele was 8.8.
---Association with NOS1
Excess of nitric oxide (NO) has been shown to exert neurotoxic effects in the brain. Moreover, inhibition of 2 enzyme isoforms of nitric oxide synthase (NOS; see 163731), neuronal NOS (nNOS) and inducible NOS (iNOS), results in neuroprotective effects in the MPTP model of PD. Levecque et al. (2003) performed a community-based case-control study of 209 PD patients enrolled in a French health insurance organization for agricultural workers and 488 European controls. Associations were observed with a G-to-A polymorphism in exon 22 of iNOS, designated iNOS 22 (OR for AA carriers, 0.50; 95% CI, 0.29-0.86; p = 0.01), and a T-to-C polymorphism in exon 29 of nNOS, designated nNOS 29 (OR for carriers of the T allele, 1.53; 95% CI, 1.08-2.16; p = 0.02). No association was observed with a T-to-C polymorphism in exon 18 of nNOS, designated nNOS 18. Moreover, a significant interaction of the nNOS polymorphisms with current and/or past cigarette smoking was found (nNOS 18, p = 0.05; nNOS 29, p = 0.04). Levecque et al. (2003) suggested that NOS1 may be a modifier gene in PD.
---Association with NAT2
Chan et al. (2003) found that the slow acetylator (243400) genotype for N-acetyltransferase-2 (NAT2; 612182) was associated with PD in Hong Kong Chinese. The frequency of slow acetylator genotype was significantly higher in 99 patients with PD than in 126 control subjects (68.7% vs 28.6%) with an odds ratio of 5.53 after adjusting for age, sex, and smoking history. In a subgroup analysis, smoking had no modifying effect on the association between genotype and PD.
---Association with GSTO1
Li et al. (2002) reported genetic linkage of a locus controlling age at onset in Alzheimer disease (AD; 104300) and PD to a 15-cM region on chromosome 10q. Li et al. (2003) combined gene expression studies on hippocampus obtained from AD patients and controls with their previously reported linkage data to identify 4 candidate genes. Allelic association studies for age-at-onset effects in 1,773 AD patients and 1,041 relatives and 635 PD patients and 727 relatives further limited association to GSTO1 (605482) (p = 0.007) and a second transcribed member of the GST omega class, GSTO2 (612314) (p = 0.005), located next to GSTO1. The authors suggested that GSTO1 may be involved in the posttranslational modification of IL1B.
For discussion of a possible association between Parkinson disease and variation in the PARL gene, see 607858.0001.
For discussion of a possible association between Parkinson disease and variation in the ABCA7 gene, see 605414.
For discussion of a possible association between Parkinson disease and variation in the RIC3 gene, see 610509.0001.
Exclusion Studies
Parboosingh et al. (1995) failed to find pathogenic mutations in either copper/zinc (147450) or manganese (147460) superoxide dismutase or in catalase (115500) in a single-strand conformation analysis of 107 unrelated patients with Parkinson disease, which included both familial and sporadic cases.
Mutations in the LRRK2 gene (609007) and the GBA gene commonly predispose to PD in individuals of Ashkenazi Jewish descent. Gan-Or et al. (2010) screened a cohort of 600 Ashkenazi PD patients for the common LRRK2 G2019S mutation (609007.0006) and for 8 GBA mutations. Among all patients, 117 (19.5%) were heterozygous for GBA mutations, and 82 (13.7%) were heterozygous for the LRRK2 G2019S mutation, including 8 patients carrying both GBA and LRRK2 mutations. There were 6 (1.0%) homozygotes or compound heterozygotes GBA mutations carriers, and 1 (0.2%) patient homozygote for G2019S. Carriers of LRRK2 G2019S or GBA mutations had a significantly earlier average age at onset (57.5 and 57.7 years) than noncarriers (61.0 years); the 8 with mutations in both genes had a similar average age at onset (57.4 years). A phenotypic comparison of those with the G2019S mutation, GBA mutations, and noncarriers of these mutations showed that more of those with the G2019S mutation reported muscle stiffness/rigidity (p = 0.007) and balance disturbances (p = 0.008), while more GBA mutation carriers reported slowness/bradykinesia (p = 0.021). However, the most common presenting symptom in both groups was tremor (about 50%). These results suggested distinct effects of LRRK2 or GBA mutations on the initial symptoms of PD in some cases.
Nussbaum and Polymeropoulos (1997) stated that the motor symptoms in Parkinson disease are generally thought to result from the deficiency or dysfunction of dopamine or dopaminergic neurons in the substantia nigra, regardless of etiology.
Auluck et al. (2002) found that Lewy bodies and Lewy neurites in postmortem brain tissue from Parkinson disease patients immunostained for the molecular chaperones HSP70 (see 140550) and HSP40 (see 604572), suggesting that chaperones may play a role in Parkinson disease progression, as was demonstrated in their studies in flies carrying mutated alpha-synuclein (163890) in which coexpression of human HSP70 mitigated the loss of dopaminergic neurons.
Botella-Lopez et al. (2006) found increased levels of a 180-kD reelin (RELN; 600514) fragment in CSF from 19 patients with AD compared to 11 nondemented controls. Western blot and PCR analysis confirmed increased levels of reelin protein and mRNA in tissue samples from the frontal cortex of AD patients. Reelin was not increased in plasma samples, suggesting distinct cellular origins. The reelin 180-kD fragment was also increased in CSF samples of other neurodegenerative disorders, including frontotemporal dementia, PSP, and PD.
Cooper et al. (2006) found that the earliest defect following alpha-synuclein expression in yeast was a block in endoplasmic reticulum-to-Golgi vesicular trafficking. In a genomewide screen, the largest class of toxicity modifiers were proteins functioning at this same step, including the Rab guanosine triphosphate Ypt1p, which associated with cytoplasmic alpha-synuclein inclusions. Elevated expression of Rab1 (179508), the mammalian Ypt1 homolog, protected against alpha-synuclein-induced dopaminergic neuron loss in animal models of PD. Thus, Cooper et al. (2006) concluded that synucleinopathies may result from disruptions in basic cellular functions that interface with the unique biology of particular neurons to make them especially vulnerable.
Outeiro et al. (2007) identified a potent inhibitor of sirtuin-2 (604480) and found that inhibition of SIRT2 rescued alpha-synuclein toxicity and modified inclusion morphology in a cellular model of Parkinson disease. Genetic inhibition of SIRT2 via small interfering RNA similarly rescued alpha-synuclein toxicity. Furthermore, the inhibitors protected against dopaminergic cell death both in vitro and in a Drosophila model of PD. Outeiro et al. (2007) concluded that their results suggest a link between neurodegeneration and aging.
Muqit et al. (2006) provided a review of the role of mitochondrial dysfunction, including oxidative damage and apoptosis, in the pathogenesis of Parkinson disease.
Elstner et al. (2009) performed whole-genome expression profiling of isolated substantia nigra neurons taken from 8 patients with PD and 9 controls. Four differentially expressed genes were identified in candidate PD pathways: MTND2 (516001, p = 7.14 x 10(-7)); PDXK (179020, p = 3.27 x 10(-6)); SRGAP3 (606525, p = 5.65 x 10(-6)); TRAPPC4 (610971, p = 5.81 x 10(-6)). Population-based studies found an association between rs2010795 in the PDXK gene and increased risk of PD in German (p = 0.00032), British (p = 0.028), and Italian (p = 0.0025) cohorts (combined p = 1.2 x 10(-7); OR of 1.3) totaling 1,232 PD patients and 2,802 controls. Elstner et al. (2009) suggested that vitamin B6 status and metabolism may influence disease risk in PD. However, neither Guella et al. (2010) nor Vilarino-Guell et al. (2010) could replicate the association with rs2010795 in their respective studies of 920 Italian PD patients and 920 Italian controls and of 6 independent populations from Europe, North America, and Asia totaling 1,977 PD patients and 1,907 controls.
In brains from patients with Parkinson disease, Minones-Moyano et al. (2011) found decreased expression of MIRN34B (611374) and MIRN34C (611375) in areas with variable neuropathologic affectation at different clinical stages of the disease, including the amygdala, frontal cortex, substantia nigra, and cerebellum. Misregulation of MIRN34B/C was detected in pre-motor stages of the disease as well, particularly in the amygdala. Depletion of MIRN34B or MIRN34C in differentiated dopaminergic neuronal cells resulted in a moderate reduction in cell viability that was accompanied by altered mitochondrial function and dynamics, oxidative stress, and reduction in total cellular ATP content. Downregulation of these miRNAs was associated with a decrease in the expression of DJ1 (602533) and PARK2 (602544), 2 genes associated with PD, in cell studies and in patient brain tissue. The findings suggested that early deregulation of MIRN34B and MIRN34C can trigger downstream transcriptome alterations underlying mitochondrial dysfunction and oxidative stress, which ultimately compromise cell viability in PD.
Raj et al. (2014) performed an expression quantitative trait locus (eQTL) study of purified CD4 (186940)+ T cells and monocytes, representing adaptive and innate immunity, in a multiethnic cohort of 461 healthy individuals. Context-specific cis- and trans-eQTLs were identified, and cross-population mapping allowed, in some cases, putative functional assignment of candidate causal regulatory variants for disease-associated loci. Raj et al. (2014) noted an overrepresentation of monocyte-specific eQTLs among Alzheimer disease (104300) and Parkinson disease variants, and of T cell-specific eQTLs among susceptibility alleles for autoimmune diseases, including rheumatoid arthritis (180300) and multiple sclerosis (126200). Raj et al. (2014) concluded that this polarization implicates specific immune cell types in these diseases and points to the need to identify the cell-autonomous effects of disease susceptibility variants.
Using an unbiased screen targeting endogenous gene expression, Mittal et al. (2017) discovered that the beta-2-adrenoreceptor (B2AR; 109690) is a regulator of the alpha-synuclein gene (SNCA; 163890). B2AR ligands modulate SNCA transcription through histone H3 lysine-27 acetylation (H3K27ac) of its promoter and enhancers. Over 11 years of follow-up in 4 million Norwegians, the B2AR agonist salbutamol, a brain-penetrant asthma medication, was associated with reduced risk of developing PD (rate ratio, 0.66; 95% confidence interval, 0.58 to 0.76). Conversely, a B2AR antagonist, propanolol, correlated with increased risk. B2AR activation protected model mice and patient-derived cells. Thus, Mittal et al. (2017) conclude that B2AR is linked to transcription of alpha-synuclein and risk of PD in a ligand-specific fashion and constitutes a potential target for therapies.
Sulzer et al. (2017) showed that a defined set of peptides that are derived from alpha-synuclein (163890) act as antigenic epitopes displayed by these alleles and drive helper and cytotoxic T cell responses in patients with Parkinson disease. Sulzer et al. (2017) suggested that these responses may explain the association of Parkinson disease with specific MHC alleles.
Burbulla et al. (2017) studied dopaminergic neurons derived from patients with idiopathic and familial (homozygous for DJ1 c.192G-C, 602533.0005) Parkinson disease. The authors identified a time-dependent pathologic cascade beginning with mitochondrial oxidant stress, leading to oxidized dopamine accumulation, and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and alpha-synuclein accumulation. This toxic cascade was observed in human, but not in mouse, Parkinson disease neurons at least in part because of species-specific differences in dopamine metabolism. Increasing dopamine synthesis or alpha-synuclein amounts in mouse midbrain neurons recapitulated pathologic phenotypes observed in human neurons. Thus, Burbulla et al. (2017) dopamine oxidation represents an important link between mitochondrial and lysosomal dysfunction in Parkinson disease pathogenesis.
Trenkwalder et al. (1995) used a door-to-door survey to investigate the prevalence of parkinsonism in a rural Bavarian population of individuals older than 65 years. In this population, the prevalence of Parkinson disease was 0.71%; drug-induced parkinsonism, 0.41%; vascular parkinsonism, 0.20%; multiple systems atrophy, 0.31%; Fahr disease, 0.10%; and normal pressure hydrocephalus, 0.41%. Fifty percent of these cases were newly diagnosed.
In a community-based survey of Singaporeans (9,000 Chinese, 3,000 Malays, and 3,000 Indians) aged 50 years and older, Tan et al. (2004) found that the prevalence rate of PD was approximately 0.30%, which is comparable to that of Western countries.
In a study of over 14,000 twin pairs in the Swedish Twin Registry, Wirdefeldt et al. (2004) found that only 2 twin pairs were concordant for PD, suggesting that environmental factors were more important in the development of the disease in this population.
Parkinson disease was first described by physician James Parkinson as a 'shaking palsy' in 1817. Stien (2005) proposed that William Shakespeare (1564-1616) referred to the disease as a 'palsy' of old age in several of his plays, indicating that the first European reference to the disease occurred in the late 16th century.
Zhang et al. (2006) provided a detailed review of early Chinese descriptions of Parkinson disease, including contemporary therapeutic recommendations. The evidence from classic sources of traditional Chinese medicine strongly suggested that PD was known to medical scholars in China as early as 425 B.C.; the first clear description of a clinical case occurred during the Jin dynasty in late 12th century A.D.
Clarke et al. (2000) studied the kinetics of neuronal death in 12 models of photoreceptor degeneration, hippocampal neurons undergoing excitotoxic cell death, a mouse model of cerebellar degeneration, and in Parkinson and Huntington (143100) diseases. In all models the kinetics of neuronal death were exponential and better explained by mathematical models in which the risk of cell death remains constant or decreases exponentially with age. These kinetics argue against the cumulative damage hypothesis; instead, the time of death in any neuron is random. Clarke et al. (2000) argued that their findings are most simply accommodated by a '1-hit' biochemical model in which mutation imposes a mutant steady state on the neuron and a single event randomly initiates cell death. This model appears to be common to many forms of neurodegeneration and has implications for therapeutic strategies in that the likelihood that a mutant neuron can be rescued by treatment is not diminished by age, and therefore treatment at any stage of illness is likely to confer benefit.
Progressive postnatal depletion of dopaminergic cells has been demonstrated in weaver mice, a mouse model of Parkinson disease associated with homozygosity for a mutation in the H54 region of Girk2, a putative G protein inward rectifier protein potassium channel. Bandmann et al. (1996) found no mutations of the pore region in KCNJ6 (600877), the human homolog, in 50 cases of Parkinson disease, 23 of which were index cases of familial Parkinson disease.
Transgenic Drosophila expressing human alpha-synuclein carrying the ala30-to-pro (A30P; 163890.0002) mutation faithfully replicate essential features of human Parkinson disease, including age-dependent loss of dopaminergic neurons, Lewy body-like inclusions, and locomotor impairment. Scherzer et al. (2003) characterized expression of the entire Drosophila genome at presymptomatic, early, and advanced disease stages. Fifty-one signature transcripts were tightly associated with A30P alpha-synuclein expression. At the presymptomatic stage, expression changes revealed specific pathology. In age-matched transgenic Drosophila expressing the arg406-to-trp mutation in tau (157140.0003), the transcription of mutant alpha-synuclein-associated genes was normal, suggesting highly distinct pathways of neurodegeneration.
Landau et al. (2005) found that Fas (TNFRSF6; 134637)-deficient lymphoproliferative mice developed a PD phenotype, characterized by extensive nigrostriatal degeneration accompanied by tremor, hypokinesia, and loss of motor coordination, after treatment with MPTP at a dose that caused no phenotype in wildtype mice. Mice with mutated Fasl (TNFSF6; 134638) and generalized lymphoproliferative disease had an intermediate phenotype. Treatment of cultured midbrain neurons with Fasl to induce Fas signaling protected them from MPTP toxicity. Mice lacking only Fas exon 9, which encodes the death domain, but retaining the intracellular Fas domain and cell surface expression of Fas, were resistant to MPTP. Peripheral blood lymphocytes from patients with idiopathic PD showed a highly significant deficit in their ability to upregulate Fas after mitogen stimulation. Landau et al. (2005) concluded that reduced FAS expression increases susceptibility to neurodegeneration and that FAS has a role in neuroprotection.
Therapeutic Strategies
Kordower et al. (2000) tested lentiviral vector delivery of glial cell line-derived neurotrophic factor (GDNF; 600837), or lenti-GDNF, for its trophic effects upon degenerating nigrostriatal neurons in nonhuman primate models of Parkinson disease. The authors injected lenti-GDNF into the striatum and substantia nigra of nonlesioned aged rhesus monkeys or young adult rhesus monkeys treated 1 week prior with MPTP, a neurotoxin known to specifically damage dopamine neurons. Extensive GDNF expression with anterograde and retrograde transport was seen in all animals. In aged monkeys, lenti-GDNF augmented dopaminergic function. In MPTP-treated monkeys, lenti-GDNF reversed functional deficits and completely prevented nigrostriatal degeneration. Additionally, lenti-GDNF injections to intact rhesus monkeys revealed long-term gene expression (8 months). In MPTP-treated monkeys, lenti-GDNF treatment reversed motor deficits in a hand-reach task. Kordower et al. (2000) concluded that GDNF delivery using a lentiviral vector system can prevent nigrostriatal degeneration and induce regeneration in primate models of PD and might be a viable therapeutic strategy for PD patients.
Luo et al. (2002) noted that a disinhibited and overactive subthalamic nucleus (STN) alters basal ganglia network activity in PD, and that electrical inhibition, pharmacologic silencing, and STN ablation can improve the motor symptoms in PD, presumably by leading to suppression of firing activity of neurons in the substantia nigra (SN). Using a recombinant adeno-associated virus to transduce excitatory glutaminergic neurons in the rat STN with glutamic acid decarboxylase (GAD), the enzyme that catalyzes synthesis of the inhibitory neurotransmitter GABA, Luo et al. (2002) showed that the neurons expressed the GAD gene and changed from largely excitatory to predominantly inhibitory, resulting in decreased excitatory and increased inhibitory response in the substantia nigra. Moreover, the increased inhibitory tone provided neuroprotection to the dopaminergic cells in response to toxic insult. Rats with the transduced gene showed significant improvement from the parkinsonian behavioral phenotype. Luo et al. (2002) emphasized the plasticity in neurotransmission in the mammalian brain.
Teismann et al. (2003) showed that cyclooxygenase-2 (COX2; 600262), the rate-limiting enzyme in prostaglandin E2 synthesis, is upregulated in brain dopaminergic neurons of both PD and the MPTP mouse model of that disorder. They demonstrated further that targeting COX2 does not protect against MPTP-induced dopaminergic neurodegeneration by mitigating inflammation. Instead, they provided evidence that COX2 inhibition prevents the formation of the oxidant species of dopamine-quinone, which has been implicated in the pathogenesis of PD. This study supported a critical role for COX2 in both the pathogenesis and selectivity of the PD neurodegenerative process. Because of the safety record of the COX2 inhibitors, and their ability to penetrate the blood-brain barrier, these drugs may be therapies for PD.
The striatum is a major forebrain nucleus that integrates cortical and thalamic afferents and forms the input nucleus of the basal ganglia. Striatal projection neurons target the substantia nigra pars reticulata (direct pathway) or the lateral globus pallidus (indirect pathway). Kreitzer and Malenka (2007) showed that excitatory synapses onto indirect-pathway medium spiny neurons exhibit higher release probability and larger NMDA receptor currents than direct-pathway synapses. Moreover, indirect-pathway medium spiny neurons selectively express endocannabinoid-mediated long-term depression (eCB-LTD), which requires dopamine D2 receptor (126450) activation. In models of Parkinson disease, indirect-pathway eCB-LTD is absent but is rescued by a D2 receptor agonist or inhibitors of endocannabinoid degradation. Administration of these drugs together in vivo in mice reduced parkinsonian motor deficits, suggesting that endocannabinoid-mediated depression of indirect-pathway synapses has a critical role in the control of movement.
Kravitz et al. (2010) reported direct activation of basal ganglia circuitry in vivo, using optogenetic control of direct- and indirect-pathway medium spiny projection neurons, achieved through Cre-dependent viral expression of channelrhodopsin-2 in the striatum of BAC transgenic mice expressing Cre recombinase under control of regulatory elements for the dopamine D1 (126449) or D2 receptors. Bilateral excitation of indirect-pathway medium spiny projection neurons elicited a parkinsonian state distinguished by increased freezing, bradykinesia, and decreased locomotor initiations. In contrast, activation of direct-pathway medium spiny projection neurons reduced freezing and increased locomotion. In a mouse model of Parkinson disease, activation of the direct pathway completely rescued deficits in freezing, bradykinesia, and locomotor initiation. Kravitz et al. (2010) concluded that their data establish a critical role for basal ganglia circuitry in the bidirectional regulation of motor behavior and indicate that modulation of direct-pathway circuitry may represent an effective therapeutic strategy for ameliorating parkinsonian motor deficits.
Chan et al. (2007) found that dopamine-containing neurons in the substantia nigra in mice relied on L-type voltage-gated calcium channels (see, e.g., CACNA1S, 114208) to drive pacemaking. The reliance on these calcium channels increased with age, and juvenile neurons tended to use sodium-powered cation channels. The mechanism used by juvenile neurons remained latent in adulthood, but pharmacologic (isradipine) or gene-mediated blocking of the calcium channels in adult neurons induced a reversion to the juvenile form of pacemaking. Such blocking of calcium influx protected dopamine-containing neurons in both in vitro and in vivo mouse models of Parkinson disease. The findings were consistent with a theory of pathogenesis in which activity-dependent calcium influx results in intracellular calcium accumulation that becomes toxic to these neurons with age.
Sotnikova et al. (2006) developed a novel acute mouse model of severe dopamine deficiency using Dat (SLC6A3; 126455)-null mice and pharmacologic inhibition of tyrosine hydroxylase. Dopamine-deficient Dat-null (DDD) mice demonstrated severe akinesia, rigidity, tremor, and ptosis, similar to behaviors observed in patients with Parkinson disease. Interestingly, DDD mice were able to swim in water, indicating that certain movements and conditions can occur independently of dopamine. Dopamine agonists such as L-DOPA temporarily restored locomotion in DDD mice, and amphetamine derivatives showed effectiveness in reducing motor abnormalities in DDD mice. Sotnikova et al. (2006) noted that the DDD mouse model provides a unique opportunity to screen potential therapeutic agents for the treatment of Parkinson disease.
Berman et al. (2011) found that Slc1a1 (133550)-null mice developed age-dependent progressive loss of dopaminergic neurons in the substantia nigra, with more than 40% of these neurons lost by age 12 months, and microglial activation in the substantia nigra. Mutant mice showed impaired motor performance compared to wildtype mice. These features were similar to those found in humans with Parkinson disease. Dopaminergic neurons in the Slc1a1-null mice showed evidence of increased oxidative stress. Long-term treatment of mutant mice with N-acetylcysteine resulted in increased levels of glutathione, prevented dopaminergic neuronal loss, and resulted in improved motor performance. Berman et al. (2011) suggested that the Slc1a1-null mouse may be a useful model for the chronic neuronal oxidative stress that occurs in PD.
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