Genetic Basis of Parkinson Disease

Neurosurg Focus 28 (1):E7, 2010

Genetic basis of Parkinson disease

Ge o r g i a Xiromerisiou , M.D.,1 Ef t h i m i o s Da r d i o t i s , M.D.,1,2 Va ï a Ts i m o u r t o u , M.D.,2 Pe r s a Ma r i a Ko u n t r a , M.D.,2 Konstantinos N. Pa t e r a k i s , M.D.,3 Ef t y c h i a Z. Ka p s a l a k i , M.D.,4 Ko s t a s N. Fo u n t a s , M.D.,3 a n d Ge o r g i o s M. Ha d j i g e o r g i o u , M.D.1,2 1Institute for Biomedical Technology (BIOMED), Centre for Research and Technology—Thessaly (CERETETH); 2Department of Neurology, Laboratory of Neurogenetics; 3Department of Neurosurgery; and 4Department of Diagnostic Radiology, University of Thessaly, University Hospital of Larissa, Greece

Over the past few years, considerable progress has been made in understanding the molecular mechanisms of Parkinson disease (PD). Mutations in certain genes are found to cause monogenic forms of the disorder, with autosomal dominant or autosomal recessive inheritance. These genes include alpha-synuclein, parkin, PINK1, DJ-1, LRRK2, and ATP13A2. The monogenic variants are important tools in identifying cellular pathways that shed light on the pathogenesis of this disease. Certain common genetic variants are also likely to modulate the risk of PD. In- ternational collaborative studies and meta-analyses have identified common variants as genetic susceptibility risk/ protective factors for sporadic PD. (DOI: 10.3171/2009.10.FOCUS09220)

Ke y Wo r d s • Parkinson disease • genetic association study • polymorphism • gene mutation

a r k i n s o n disease is the second most common neu- ance of certain clinical features, and also the disease pro- rodegenerative disorder after Alzheimer disease. gression. The average age at onset is between 60 and 80 In this paper, a concise summary of the main genes Pyears, and ~ 1% of the general population older than 65 responsible for monogenic forms of PD (Table 1), and is affected.12,89 some of the common genetic variants that may play a role Although PD appears to be sporadic in most cases, in the disease, is provided. linkage and positional cloning studies were instrumental in the identification of certain genes that cause familial forms of the disease that feature autosomal dominant Monogenic Forms of PD or autosomal recessive inheritance.12,89 Approximately Alpha-synuclein (SNCA-PARK1/PARK4) is cen- 5–10% of patients with the clinical picture of PD carry tral to the pathophysiological mechanisms of familial a mutation in one of the known genes that cause mono- and sporadic PD. This protein is the major component of genic forms of the disorder.12,89 There is some evidence Lewy bodies and Lewy neuritis in PD, and also in oth- that these genes may also play a role in the much more er synucleinopathies. Three missense mutations (A53T, common sporadic form of the disease. The biochemical A30P, E64 K), and duplications or triplications of the lo- function of these genes can underlie various pathoge- cus containing SNCA have been identified previously in netic pathways, such as oxidative stress, mitochondrial families with autosomal dominant PD.29,42,65,67,76,77,90,92 The dysfunction, disturbance in protein quality control, and phenotype of patients with SNCA point mutations is that altered kinase activity that may lead to PD. of levodopa-responsive parkinsonism in patients with a The vast majority of cases of this disorder are spo- relatively young age at onset, rapid progression, and high radic, resulting from complex interactions among genes, prevalence of dementia, psychiatric, and autonomic dis- and between genes and environmental factors. Genetic turbances. Patients with duplications resemble those with variations may be susceptibility factors for disease that idiopathic PD,10 and those with triplications have earlier also affect penetrance, age at onset, severity, the appear- onset, faster disease progression, severe dementia, and frequent dysautonomia.23,76 There is consensus that any Abbreviations used in this paper: DBS = deep brain stimulation; change in the levels of alpha-synuclein expression or the PD = Parkinson disease; SNP = single nucleotide polymorphism. presence of mutations in alpha-synuclein has a toxic ef-

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TABLE 1: Genetic loci and genes associated with monogenic forms of PD*

Locus Gene Inheritance & Comments OMIM No. PARK1 SNCA AD; 1st PD gene identified 168601 PARK2 PRKN AR; most common cause of recessive juvenile PD 602544 PARK3 SPR? AD 602404 & 182125 PARK4 SNCA AD 168601 PARK5 UCHL1 AD 191342 PARK6 PINK1 AR; 2nd most common cause of recessive juvenile PD 605909 PARK7 DJ-1 AR 606324 PARK8 LRRK2 AD; most common cause of dominant PD 607060 PARK9 ATP13A2 AR; PD plus dementia & spasticity 606693 PARK10 unknown ? 606852 PARK11 GIGYF2? AD 607688 PARK12 unknown ? 300557 PARK13 Omi/HTRA2 ? 610297 PARK14 PLA2G6 AR; PD plus adult-onset dystonia 612953 PARK15 FBXO7 AR; PD plus dementia & spasticity 260300

* AD = autosomal dominant; AR = autosomal recessive; OMIM = Online Mendelian Inheritance in Man; ? = controversial or unidentified. fect on dopaminergic neurons.18 Alpha-synuclein mono- parkinsonism.81,82 This gene links PD to mitochondrial mers interact under certain circumstances to form proto- dysfunction and oxidative stress as it encodes a primar- fibrils or fibrillar β-pleated sheets.84,86,89 Toxicity caused ily mitochondrial protein kinase. This protein may exert a by protofibrils may involve the leakage of dopamine from protective effect on the cell.2,69 No pathological mechanism synaptic vesicles because of perforation of the vesicular has yet been reported in patients with PINK1 mutations. membranes by these protofibrils.29 This may account for Patients with mutations in this gene are characterized by the selective toxicity of alpha-synuclein in the dopamine- early onset of parkinsonism (between 32 and 48 years producing neurons of the substantia nigra.13,56,84 of age), with slow progression and sustained response to Parkin (PRKN, PARK2) was the first gene identi- levodopa. There are also some indications that they have a fied for an autosomal recessive form of PD.1,5,35,40,83 Par- higher prevalence of psychiatric disturbances.3,17 kin protein localizes, although not predominantly, to the The third locus for autosomal recessive juvenile par- synapse and associates with membranes. Its main func- kinsonism was mapped also to chromosome 1p36, and the tion is as an ubiquitin ligase in the cellular ubiquitina- gene was identified as the oncogene DJ-1 (PARK7).6 The tion protein degradation pathway. Severe and selective function of the DJ-1 protein is not entirely clear. The main degeneration in the substantia nigra pars compacta but hypothesis is that it acts as a sensor for oxidative stress, without Lewy bodies has been described, suggesting that providing neuroprotection in situations of increased de- the disease may differ in some important ways from typi- mand.7,93 Parkinson disease causing DJ-1 mutations is rare cal idiopathic PD.35,68,83,91 Parkin mutations turned out to and accounts for only ~ 1–2% of early-onset autosomal be a very common cause of parkinsonism. All types of recessive PD cases. The phenotype closely resembles that mutations; missense mutations, nonsense mutations, and found in patients with parkin and PINK1 mutations.6 The exonic rearrangements were identified. The vast major- associated pathological characteristics are still unknown, ity of patients with parkin mutations manifest the disease because no autopsies have been reported. before the age of 40 years, with slow progression, but with Mutations in LRRK2 (PARK8) have been found in a levodopa-associated fluctuations and dyskinesias occur- large number of patients with PD.63,94 More than 40 dif- ring early and frequently. Unusual features such as focal ferent variants, almost all missense mutations, have been dystonia, early postural instability, and autonomic failure reported.4,37 The G2019S mutation in particular was de- may also be present. tected in 5–6% of autosomal dominant familial PD cases Mutations in the PINK1 gene (PARK6) have also been and in 1–2% of sporadic cases.28,46,62,80 Specific popula- identified as a cause of autosomal recessive early-onset tions such as Ashkenazi Jews and North African Arabs

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Unauthenticated | Downloaded 10/02/21 01:54 AM UTC Genetic basis of Parkinson disease were found to have an even higher prevalence.45,62 The Neurosurgical Treatment in Familial PD LRRK2 is a large protein with multiple protein interactions and catalytic domains that have possible roles in The identification of inherited forms of PD has also intracellular signaling pathways.58,85 Some pathogenetic helped in developing a more appropriate application mutations seem to be associated with an increase of ki- of neurosurgical treatments of the disease. Deep brain nase activity, which appears to be necessary for neuro- stimulation provides symptomatic benefits to patients 32,39 with idiopathic PD in terms of both motor activity and toxicity in vitro. Although LRRK2 was not found to 72 interact with either alpha-synuclein or tau, the identifica- quality of life. In hereditary PD, DBS is an efficacious symptomatic treatment for patients with parkinsonism tion of Lewy body or neurofibrillary tangle pathological and mutation of the parkin and PINK1 genes.8,73 Pa- features in patients with LRRK2 mutations suggested a tients with parkin mutations are specifically expected to possible common role of LRRK2 in the processing of be very good candidates for DBS and to benefit more those two proteins.85 The phenotype of LRRK2 mutation and longer than other patients because of their younger carriers is that of idiopathic PD, although the whole clini- age at onset, lower daily doses of levodopa, and slower cal picture is more benign. disease progression.8,51,73 The response to DBS among patients carrying mutations of the LRRK2 gene is not Other Genes and Loci well established.46,75 There are some studies that show that the response to DBS was worse among patients with The ATP13A2 gene is mapped at the PARK9 locus the R1441G mutation in LRRK2 compared with patients and is responsible for Kufor-Rakeb disease, a recessive, with idiopathic PD. juvenile-onset, atypical Parkinsonism with pyramidal 71 Based on the aforementioned findings, we conclude degeneration and cognitive dysfunction. The ATP13A2 that the effectiveness of DBS in different genetic forms gene encodes a large lysosomal P-type adenosine triphos- of PD has not been studied adequately. The main reason phatase, which is involved in the lysosomal degradation for this is that patient selection is based predominantly pathway that clears SNCA aggregates. Lysosomal dys- on clinical criteria.9,52 A multidisciplinary approach in- function caused by mutations in this gene might contrib- 83 volving a neurosurgeon, a neurologist, and a neuropsy- ute to the pathogenesis of parkinsonism. chologist is important to determine the appropriate surgi- A heterozygous missense mutation in the ubiquitin cal candidate. The best prognostic indicator of a patient’s carboxy-terminal hydrolase L1 gene (UCHL1, PARK5), suitability for DBS surgery is his/her response to levodo- which is located on chromosome 4p, has been identified pa.9 The patient’s age also is another major factor deter- in a single affected family of German ancestry. However, mining how an individual will cope with the surgical 87 whether UCHL1 is really a PD gene is not clear yet. procedure and behave postoperatively.74 Based on these Mutations in the glucocerebrosidase gene (GBA) criteria, many patients with genetic forms of the disease (which has not been assigned a PARK locus yet) are the who have a sustained response to levodopa38 or atypical cause of a recessive lysosomal storage disorder—Gaucher symptoms are excluded from this procedure. As a result, disease. More than 200 mutations have been described in it is impossible, based solely on clinical characteristics of GBA. Phenotypes of Gaucher disease and PD do not over- monogenic PD forms, to study the effectiveness of DBS lap significantly, but the first indication for a relationship in these patients. Another reason for this is that most pa- between the two actually came from clinical descriptions. tients who have undergone DBS surgery are not screened Mutations in GBA have a conspicuously high prevalence for mutations in various genes responsible for monogenic in patients with PD.57 Between 2 and 4% of Caucasian forms of the disease. patients with PD have been found to have mutations in The detailed evaluation of these patients and the ge- GBA. Those variants are likely to act as risk factors rath- netic analysis based on criteria such as the family history, er than as high-penetrance disease genes.59 The nature of phenotype, age at onset, and response to levodopa are of the association between PD and Gaucher disease remains great importance. However, larger series of patients with elusive. However, the pathogenic mechanisms leading to mutations and longer follow-ups will be needed for evi- PD in carriers of mutant GBA may be related to the faulty dence of specific genotype-related differences. processing of toxic proteins, aggravated by the relative Another matter worth discussing is that there are decrease in GBA activity and accumulation of glucoce- also no studies showing the optimal DBS target based rebrosidase.50,61 Moreover, recent findings indicate that on genetics. Generally the literature demonstrates a trend Gaucher disease and PD share pathophysiological fea- that the subthalamic nucleus may be more efficient in tures.88 managing the symptoms of PD, based on institutional Other mendelian forms of PD remain to be identi- experience, surgical and programming management, fied. Either the causal genes at several loci have not yet lower current requirements, and significant reduction in been identified (PARK12), or the role of the candidate dopaminergic medication.38,41,66 For these reasons, all genes at these loci is still controversial (PARK3, PARK10, of the previous studies in patients with mutations have PARK13). Two novel genes, the FBXO7 (PARK15), a referred to the effectiveness of DBS of the subthalamic member of the F-box family of proteins active in the nucleus.30,51,75 Maybe the genetic forms of the disease with ubiquitin-proteasome protein degradation pathway,14 and the different neuropathological characteristics will enable the PLA2G6 gene (PARK14) on chromosome 22, have deciphering of the mechanisms of DBS on the basis of also been identified in families with atypical PD.33 the function and pathophysiological characteristics of the

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Unauthenticated | Downloaded 10/02/21 01:54 AM UTC G. Xiromerisiou et al. cortico-basal-thalamo-cortical loops when different DBS tion approach to unravel genetic susceptibility factors. targets are being applied to them. Genome-wide association studies of PD, which use haplotype tagging strategies to study variation across the entire human genome, provided little evidence until now about Genetic Susceptibility Factors in Sporadic PD genetic variants that influence the risk for disease. A Monogenic forms represent < 10% of cases of PD. 2-stage genome-wide association study with a 200-SNP Common PD, on the other hand, is thought to result from map, and a 1-stage study with more informative mark- complex interactions involving genetic and environmental ers found no positive associations.25,54 The most strongly risk factors. The discovery that 1-methyl-4-phenyl tetrahy- associated SNPs identified in the 2-stage study were not dropyridine, a contaminant of a synthetic opiate, can cause replicated in a subsequent association study with a large parkinsonism through its neurotoxic metabolite, 1-methyl- number of participants.16,54 However, the combination of 4-phenylpyridinium, stimulated interest in environmental genome-wide databases with meta-analytical techniques chemical exposures as risk factors for PD.44 Many studies can improve the detection of genetic variants with small have investigated the association between PD and pesticide effect sizes. The GAK-DGKQ region on chromosome 4 use, and some, but not all, have found an association.22,70,95 has been identified by this strategy, albeit not replicated Use of well water, rural living, and agricultural employ- in a recent report.19,20 The genomic pathway approach that ment have also been implicated as risk factors, although combines SNPs with axon guidance pathway genes has studies have given conflicting results.43,95 also been applied to genome-wide association studies, On the other hand, the extent of the genetic compo- with one positive result,48 but again without replication.49 nent remains elusive. Common genetic variations (main- Genome-wide association studies require large sample se- ly SNPs) may be either susceptibility factors or disease ries and international collaborations, so probably we will modifiers, affecting penetrance, age at onset, severity, or have to wait for a few years to identify possible common disease progression. genetic risk variants and clearly understand their role in Genetic association studies that compare the fre- the disease.20,25,36,47,54 quency of putative risk alleles in cohorts of patients and controls are controversial because they have failed to reproduce the initial positive findings most of the time. Conclusions Almost 800 genetic association studies have been per- It is hoped that an understanding of the genetic basis formed so far on more than 500 genes regarding PD (see of PD will allow us to identify upstream key facts of the www.pdgene.org). The vast majority of genetic associa- pathogenesis and lead to new targeted therapeutic strate- tion studies have focused on candidate genes involved gies in the future. Large-scale multicenter collaborations, in detoxification of metabolites, dopamine metabolism, public availability of the International HapMap Project, mitochondrial function, and familial PD.78 Some of these and genome-wide association PD databases will hope- findings were exciting at the beginning because the en- fully arm researchers with information that could be used coded proteins of these genes appear to be closely linked for modifying the natural course of the disease. to the pathophysiological mechanisms of PD; however, none of these candidate gene variants have been consis- Disclosure tently replicated since then. Thus, theoretically attrac- tive, broad-based meta-analyses yielded no true common The authors report no conflict of interest concerning the mate- genetic risk variant. Potential biases include population rials or methods used in this study or the findings specified in this stratification, small sample size, misclassification, and -in paper. 36 Author contributions to the study and manuscript preparation appropriate statistical methods. include the following. Conception and design: E Dardiotis. Analysis Nevertheless, specific polymorphic variants have and interpretation of data: E Dardiotis, V Tsimourtou, PM Kountra, been validated as genetic susceptibility factors. The Rep KN Paterakis, EZ Kapsalaki. Study supervision: KN Fountas, G 1, a mixed nucleotide repeat in the promoter region of Xiromerisiou, GM Hadjigeorgiou. SNCA, has been confirmed as a risk factor.11,34,53,55,60,64 A polymorphism in microtubule-associated protein tau References has also been detected.26 The combination of risk geno- types in SNCA and microtubule-associated protein tau 1. 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