Genetic basis of Parkinson disease

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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. International collaborative studies and meta-analyses have identified common variants as genetic susceptibility risk/protective factors for sporadic PD.

Abbreviations used in this paper: DBS = deep brain stimulation; PD = Parkinson disease; SNP = single nucleotide polymorphism.

Abstract

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. International collaborative studies and meta-analyses have identified common variants as genetic susceptibility risk/protective factors for sporadic PD.

Parkinson disease is the second most common neurodegenerative disorder after Alzheimer disease. The average age at onset is between 60 and 80 years, and ~ 1% of the general population older than 65 is affected.12,89

Although PD appears to be sporadic in most cases, linkage and positional cloning studies were instrumental in the identification of certain genes that cause familial forms of the disease that feature autosomal dominant or autosomal recessive inheritance.12,89 Approximately 5–10% of patients with the clinical picture of PD carry a mutation in one of the known genes that cause monogenic forms of the disorder.12,89 There is some evidence that these genes may also play a role in the much more common sporadic form of the disease. The biochemical function of these genes can underlie various pathogenetic pathways, such as oxidative stress, mitochondrial dysfunction, disturbance in protein quality control, and altered kinase activity that may lead to PD.

The vast majority of cases of this disorder are sporadic, resulting from complex interactions among genes, and between genes and environmental factors. Genetic variations may be susceptibility factors for disease that also affect penetrance, age at onset, severity, the appearance of certain clinical features, and also the disease progression.

In this paper, a concise summary of the main genes responsible for monogenic forms of PD (Table 1), and some of the common genetic variants that may play a role in the disease, is provided.

TABLE 1:

Genetic loci and genes associated with monogenic forms of PD*

LocusGeneInheritance & CommentsOMIM No.
PARK1SNCAAD; 1st PD gene identified168601
PARK2PRKNAR; most common cause of recessive juvenile PD602544
PARK3SPR?AD602404 & 182125
PARK4SNCAAD168601
PARK5UCHL1AD191342
PARK6PINK1AR; 2nd most common cause of recessive juvenile PD605909
PARK7DJ-1AR606324
PARK8LRRK2AD; most common cause of dominant PD607060
PARK9ATP13A2AR; PD plus dementia & spasticity606693
PARK10unknown?606852
PARK11GIGYF2?AD607688
PARK12unknown?300557
PARK13Omi/HTRA2?610297
PARK14PLA2G6AR; PD plus adult-onset dystonia612953
PARK15FBXO7AR; PD plus dementia & spasticity260300

* AD = autosomal dominant; AR = autosomal recessive; OMIM = Online Mendelian Inheritance in Man; ? = controversial or unidentified.

Monogenic Forms of PD

Alpha-synuclein (SNCA-PARK1/PARK4) is central to the pathophysiological mechanisms of familial and sporadic PD. This protein is the major component of Lewy bodies and Lewy neuritis in PD, and also in other synucleinopathies. Three missense mutations (A53T, A30P, E64 K), and duplications or triplications of the locus containing SNCA have been identified previously in families with autosomal dominant PD.29,42,65,67,76,77,90,92 The phenotype of patients with SNCA point mutations is that of levodopa-responsive parkinsonism in patients with a relatively young age at onset, rapid progression, and high prevalence of dementia, psychiatric, and autonomic disturbances. Patients with duplications resemble those with idiopathic PD,10 and those with triplications have earlier onset, faster disease progression, severe dementia, and frequent dysautonomia.23,76 There is consensus that any change in the levels of alpha-synuclein expression or the presence of mutations in alpha-synuclein has a toxic effect on dopaminergic neurons.18 Alpha-synuclein monomers interact under certain circumstances to form protofibrils or fibrillar β-pleated sheets.84,86,89 Toxicity caused by protofibrils may involve the leakage of dopamine from synaptic vesicles because of perforation of the vesicular membranes by these protofibrils.29 This may account for the selective toxicity of alpha-synuclein in the dopamine-producing neurons of the substantia nigra.13,56,84

Parkin (PRKN, PARK2) was the first gene identified for an autosomal recessive form of PD.1,5,35,40,83 Parkin protein localizes, although not predominantly, to the synapse and associates with membranes. Its main function is as an ubiquitin ligase in the cellular ubiquitination protein degradation pathway. Severe and selective degeneration in the substantia nigra pars compacta but without Lewy bodies has been described, suggesting that the disease may differ in some important ways from typical idiopathic PD.35,68,83,91 Parkin mutations turned out to be a very common cause of parkinsonism. All types of mutations; missense mutations, nonsense mutations, and exonic rearrangements were identified. The vast majority of patients with parkin mutations manifest the disease before the age of 40 years, with slow progression, but with levodopa-associated fluctuations and dyskinesias occurring early and frequently. Unusual features such as focal dystonia, early postural instability, and autonomic failure may also be present.

Mutations in the PINK1 gene (PARK6) have also been identified as a cause of autosomal recessive early-onset parkinsonism.81,82 This gene links PD to mitochondrial dysfunction and oxidative stress as it encodes a primarily mitochondrial protein kinase. This protein may exert a protective effect on the cell.2,69 No pathological mechanism has yet been reported in patients with PINK1 mutations. Patients with mutations in this gene are characterized by early onset of parkinsonism (between 32 and 48 years of age), with slow progression and sustained response to levodopa. There are also some indications that they have a higher prevalence of psychiatric disturbances.3,17

The third locus for autosomal recessive juvenile parkinsonism was mapped also to chromosome 1p36, and the gene was identified as the oncogene DJ-1 (PARK7).6 The function of the DJ-1 protein is not entirely clear. The main hypothesis is that it acts as a sensor for oxidative stress, providing neuroprotection in situations of increased demand.7,93 Parkinson disease causing DJ-1 mutations is rare and accounts for only ~ 1–2% of early-onset autosomal recessive PD cases. The phenotype closely resembles that found in patients with parkin and PINK1 mutations.6 The associated pathological characteristics are still unknown, because no autopsies have been reported.

Mutations in LRRK2 (PARK8) have been found in a large number of patients with PD.63,94 More than 40 different variants, almost all missense mutations, have been reported.4,37 The G2019S mutation in particular was detected in 5–6% of autosomal dominant familial PD cases and in 1–2% of sporadic cases.28,46,62,80 Specific populations such as Ashkenazi Jews and North African Arabs were found to have an even higher prevalence.45,62 The LRRK2 is a large protein with multiple protein interactions and catalytic domains that have possible roles in intracellular signaling pathways.58,85 Some pathogenetic mutations seem to be associated with an increase of kinase activity, which appears to be necessary for neurotoxicity in vitro.32,39 Although LRRK2 was not found to interact with either alpha-synuclein or tau, the identification of Lewy body or neurofibrillary tangle pathological features in patients with LRRK2 mutations suggested a possible common role of LRRK2 in the processing of those two proteins.85 The phenotype of LRRK2 mutation carriers is that of idiopathic PD, although the whole clinical picture is more benign.

Other Genes and Loci

The ATP13A2 gene is mapped at the PARK9 locus and is responsible for Kufor-Rakeb disease, a recessive, juvenile-onset, atypical Parkinsonism with pyramidal degeneration and cognitive dysfunction.71 The ATP13A2 gene encodes a large lysosomal P-type adenosine triphosphatase, which is involved in the lysosomal degradation pathway that clears SNCA aggregates. Lysosomal dysfunction caused by mutations in this gene might contribute to the pathogenesis of parkinsonism.83

A heterozygous missense mutation in the ubiquitin carboxy-terminal hydrolase L1 gene (UCHL1, PARK5), which is located on chromosome 4p, has been identified in a single affected family of German ancestry. However, whether UCHL1 is really a PD gene is not clear yet.87

Mutations in the glucocerebrosidase gene (GBA) (which has not been assigned a PARK locus yet) are the cause of a recessive lysosomal storage disorder—Gaucher disease. More than 200 mutations have been described in GBA. Phenotypes of Gaucher disease and PD do not overlap significantly, but the first indication for a relationship between the two actually came from clinical descriptions. Mutations in GBA have a conspicuously high prevalence in patients with PD.57 Between 2 and 4% of Caucasian patients with PD have been found to have mutations in GBA. Those variants are likely to act as risk factors rather than as high-penetrance disease genes.59 The nature of the association between PD and Gaucher disease remains elusive. However, the pathogenic mechanisms leading to PD in carriers of mutant GBA may be related to the faulty processing of toxic proteins, aggravated by the relative decrease in GBA activity and accumulation of glucocerebrosidase.50,61 Moreover, recent findings indicate that Gaucher disease and PD share pathophysiological features.88

Other mendelian forms of PD remain to be identified. Either the causal genes at several loci have not yet been identified (PARK12), or the role of the candidate genes at these loci is still controversial (PARK3, PARK10, PARK13). Two novel genes, the FBXO7 (PARK15), a member of the F-box family of proteins active in the ubiquitin-proteasome protein degradation pathway,14 and the PLA2G6 gene (PARK14) on chromosome 22, have also been identified in families with atypical PD.33

Neurosurgical Treatment in Familial PD

The identification of inherited forms of PD has also helped in developing a more appropriate application of neurosurgical treatments of the disease. Deep brain stimulation provides symptomatic benefits to patients with idiopathic PD in terms of both motor activity and quality of life.72 In hereditary PD, DBS is an efficacious symptomatic treatment for patients with parkinsonism and mutation of the parkin and PINK1 genes.8,73 Patients with parkin mutations are specifically expected to be very good candidates for DBS and to benefit more and longer than other patients because of their younger age at onset, lower daily doses of levodopa, and slower disease progression.8,51,73 The response to DBS among patients carrying mutations of the LRRK2 gene is not well established.46,75 There are some studies that show that the response to DBS was worse among patients with the R1441G mutation in LRRK2 compared with patients with idiopathic PD.

Based on the aforementioned findings, we conclude that the effectiveness of DBS in different genetic forms of PD has not been studied adequately. The main reason for this is that patient selection is based predominantly on clinical criteria.9,52 A multidisciplinary approach involving a neurosurgeon, a neurologist, and a neuropsychologist is important to determine the appropriate surgical candidate. The best prognostic indicator of a patient's suitability for DBS surgery is his/her response to levodopa.9 The patient's age also is another major factor determining how an individual will cope with the surgical procedure and behave postoperatively.74 Based on these criteria, many patients with genetic forms of the disease who have a sustained response to levodopa38 or atypical symptoms are excluded from this procedure. As a result, it is impossible, based solely on clinical characteristics of monogenic PD forms, to study the effectiveness of DBS in these patients. Another reason for this is that most patients who have undergone DBS surgery are not screened for mutations in various genes responsible for monogenic forms of the disease.

The detailed evaluation of these patients and the genetic analysis based on criteria such as the family history, phenotype, age at onset, and response to levodopa are of great importance. However, larger series of patients with mutations and longer follow-ups will be needed for evidence of specific genotype-related differences.

Another matter worth discussing is that there are also no studies showing the optimal DBS target based on genetics. Generally the literature demonstrates a trend that the subthalamic nucleus may be more efficient in managing the symptoms of PD, based on institutional experience, surgical and programming management, lower current requirements, and significant reduction in dopaminergic medication.38,41,66 For these reasons, all of the previous studies in patients with mutations have referred to the effectiveness of DBS of the subthalamic nucleus.30,51,75 Maybe the genetic forms of the disease with the different neuropathological characteristics will enable deciphering of the mechanisms of DBS on the basis of the function and pathophysiological characteristics of the cortico-basal-thalamo-cortical loops when different DBS targets are being applied to them.

Genetic Susceptibility Factors in Sporadic PD

Monogenic forms represent < 10% of cases of PD. Common PD, on the other hand, is thought to result from complex interactions involving genetic and environmental risk factors. The discovery that 1-methyl-4-phenyl tetrahy-dropyridine, a contaminant of a synthetic opiate, can cause parkinsonism through its neurotoxic metabolite, 1-methyl-4-phenylpyridinium, stimulated interest in environmental chemical exposures as risk factors for PD.44 Many studies have investigated the association between PD and pesticide use, and some, but not all, have found an association.22,70,95 Use of well water, rural living, and agricultural employment have also been implicated as risk factors, although studies have given conflicting results.43,95

On the other hand, the extent of the genetic component remains elusive. Common genetic variations (mainly SNPs) may be either susceptibility factors or disease modifiers, affecting penetrance, age at onset, severity, or disease progression.

Genetic association studies that compare the frequency 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. Almost 800 genetic association studies have been performed so far on more than 500 genes regarding PD (see www.pdgene.org). The vast majority of genetic association studies have focused on candidate genes involved in detoxification of metabolites, dopamine metabolism, mitochondrial function, and familial PD.78 Some of these findings were exciting at the beginning because the encoded proteins of these genes appear to be closely linked to the pathophysiological mechanisms of PD; however, none of these candidate gene variants have been consistently replicated since then. Thus, theoretically attractive, broad-based meta-analyses yielded no true common genetic risk variant. Potential biases include population stratification, small sample size, misclassification, and inappropriate statistical methods.36

Nevertheless, specific polymorphic variants have been validated as genetic susceptibility factors. The Rep 1, a mixed nucleotide repeat in the promoter region of SNCA, has been confirmed as a risk factor.11,34,53,55,60,64 A polymorphism in microtubule-associated protein tau has also been detected.26 The combination of risk genotypes in SNCA and microtubule-associated protein tau doubles the risk of PD.27,31 Two variants in the LRRK2 gene, G2385R and R1628P, confer susceptibility to PD in Asian populations.15,21,24,80 An S18Y variant of the UCHL1 gene has been demonstrated to be protective against PD in some association studies and meta-analyses.5,79 The number of polymorphisms that have been studied until now is very large, but so far these are some of the main risk alleles for sporadic PD that seems to be robustly reproducible.

With the completion of the human “HapMap” project and the availability of the SNP databases, there is increasing interest in using the whole-genome association approach to unravel genetic susceptibility factors. 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 variants that influence the risk for disease. A 2-stage genome-wide association study with a 200-SNP map, and a 1-stage study with more informative markers found no positive associations.25,54 The most strongly associated SNPs identified in the 2-stage study were not replicated in a subsequent association study with a large number of participants.16,54 However, the combination of genome-wide databases with meta-analytical techniques can improve the detection of genetic variants with small effect sizes. The GAK-DGKQ region on chromosome 4 has been identified by this strategy, albeit not replicated in a recent report.19,20 The genomic pathway approach that combines SNPs with axon guidance pathway genes has also been applied to genome-wide association studies, with one positive result,48 but again without replication.49 Genome-wide association studies require large sample series and international collaborations, so probably we will have to wait for a few years to identify possible common genetic risk variants and clearly understand their role in the disease.20,25,36,47,54

Conclusions

It is hoped that an understanding of the genetic basis of PD will allow us to identify upstream key facts of the pathogenesis and lead to new targeted therapeutic strategies in the future. Large-scale multicenter collaborations, public availability of the International HapMap Project, and genome-wide association PD databases will hopefully arm researchers with information that could be used for modifying the natural course of the disease.

Disclosure

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author contributions to the study and manuscript preparation include the following. Conception and design: E Dardiotis. Analysis and interpretation of data: E Dardiotis, V Tsimourtou, PM Kountra, KN Paterakis, EZ Kapsalaki. Study supervision: KN Fountas, G Xiromerisiou, GM Hadjigeorgiou.

References

  • 1

    Abbas NLücking CBRicard SDürr ABonifati VDe Michele G: A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. Hum Mol Genet 8:5675741999

  • 2

    Abou-Sleiman PMMuqit MMWood NW: Expanding insights of mitochondrial dysfunction in Parkinson's disease. Nat Rev Neurosci 7:2072192006

  • 3

    Albanese AValente EMRomito LMBellacchio EElia AEDallapiccola B: The PINK1 phenotype can be indistinguishable from idiopathic Parkinson disease. Neurology 64:195819602005

  • 4

    Berg DSchweitzer KLeitner PZimprich ALichtner PBelcredi P: Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson's disease*. Brain 128:300030112005

  • 5

    Betarbet RSherer TBGreenamyre JT: Ubiquitin-proteasome system and Parkinson's diseases. Exp Neurol 191:Suppl 1S17S272005

  • 6

    Bonifati VRizzu Pvan Baren MJSchaap OBreedveld GJKrieger E: Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:2562592003

  • 7

    Canet-Avilés RMWilson MAMiller DWAhmad RMcLendon CBandyopadhyay S: The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic aciddriven mitochondrial localization. Proc Natl Acad Sci U S A 101:910391082004

  • 8

    Capecci MPassamonti LAnnesi FAnnesi GBellesi MCandiano IC: Chronic bilateral subthalamic deep brain stimulation in a patient with homozygous deletion in the parkin gene. Mov Disord 19:145014522004

  • 9

    Charles PDVan Blercom NKrack PLee SLXie JBesson G: Predictors of effective bilateral subthalamic nucleus stimulation for PD. Neurology 59:9329342002

  • 10

    Chartier-Harlin MCKachergus JRoumier CMouroux VDouay XLincoln S: Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364:116711692004

  • 11

    Chiba-Falek ONussbaum RL: Effect of allelic variation at the NACP-Rep1 repeat upstream of the alpha-synuclein gene (SNCA) on transcription in a cell culture luciferase reporter system. Hum Mol Genet 10:310131092001

  • 12

    Cookson MRXiromerisiou GSingleton A: How genetics research in Parkinson's disease is enhancing understanding of the common idiopathic forms of the disease. Curr Opin Neurol 18:7067112005

  • 13

    Cuervo AMStefanis LFredenburg RLansbury PTSulzer D: Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305:129212952004

  • 14

    Di Fonzo ADekker MCMontagna PBaruzzi AYonova EHCorreia Guedes L: FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome. Neurology 72:2402452009

  • 15

    Di Fonzo AWu-Chou YHLu CSvan Doeselaar MSimons EJRohé CF: A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson's disease risk in Taiwan. Neurogenetics 7:1331382006

  • 16

    Elbaz ANelson LMPayami HIoannidis JPFiske BKAnnesi G: Lack of replication of thirteen single-nucleotide polymorphisms implicated in Parkinson's disease: a large-scale international study. Lancet Neurol 5:9179232006

  • 17

    Ephraty LPorat OIsraeli DCohen OSTunkel OYael S: Neuropsychiatric and cognitive features in autosomal-recessive early parkinsonism due to PINK1 mutations. Mov Disord 22:5665692007

  • 18

    Eriksen JLPrzedborski SPetrucelli L: Gene dosage and pathogenesis of Parkinson's disease. Trends Mol Med 11:91962005

  • 19

    Evangelou EMaraganore DMAnnesi GBrighina LBrice AElbaz A: Non-replication of association for six polymorphisms from meta-analysis of genome-wide association studies of Parkinson's disease: large-scale collaborative study. Am J Med Genet B Neuropsychiatr Genet [epub ahead of print]2009

  • 20

    Evangelou EMaraganore DMIoannidis JP: Meta-analysis in genome-wide association datasets: strategies and application in Parkinson disease. PLoS One 2:e1962007

  • 21

    Farrer MJStone JTLin CHDächsel JCHulihan MMHaugarvoll K: Lrrk2 G2385R is an ancestral risk factor for Parkinson's disease in Asia. Parkinsonism Relat Disord 13:89922007

  • 22

    Firestone JASmith-Weller TFranklin GSwanson PLongstreth WT JrCheckoway H: Pesticides and risk of Parkinson disease: a population-based case-control study. Arch Neurol 62:91952005

  • 23

    Fuchs JNilsson CKachergus JMunz MLarsson EMSchüle B: Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication. Neurology 68:9169222007

  • 24

    Funayama MLi YTomiyama HYoshino HImamichi YYamamoto M: Leucine-rich repeat kinase 2 G2385R variant is a risk factor for Parkinson disease in Asian population. Neuroreport 18:2732752007

  • 25

    Fung HCScholz SMatarin MSimón-Sánchez JHernandez DBritton A: Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol 5:9119162006

  • 26

    Fung HCXiromerisiou GGibbs JRWu YREerola JGourbali V: Association of tau haplotype-tagging polymorphisms with Parkinson's disease in diverse ethnic Parkinson's disease cohorts. Neurodegener Dis 3:3273332006

  • 27

    Galpern WRLang AE: Interface between tauopathies and synucleinopathies: a tale of two proteins. Ann Neurol 59:4494582006

  • 28

    Gilks WPAbou-Sleiman PMGandhi SJain SSingleton ALees AJ: A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 365:4154162005

  • 29

    Goldberg MSLansbury PT Jr: Is there a cause-and-effect relationship between alpha-synuclein fibrillization and Parkinson's disease?. Nat Cell Biol 2:E115E1192000

  • 30

    Gómez-Esteban JCLezcano EZarranz JJGonzález CBilbao GLambarri I: Outcome of bilateral deep brain subthalamic stimulation in patients carrying the R1441G mutation in the LRRK2 dardarin gene. Neurosurgery 62:8578632008

  • 31

    Goris AWilliams-Gray CHClark GRFoltynie TLewis SJBrown J: Tau and alpha-synuclein in susceptibility to, and dementia in, Parkinson's disease. Ann Neurol 62:1451532007

  • 32

    Greggio EJain SKingsbury ABandopadhyay RLewis PKaganovich A: Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol Dis 23:3293412006

  • 33

    Gregory AWestaway SKHolm IEKotzbauer PTHogarth PSonek S: Neurodegeneration associated with genetic defects in phospholipase A(2). Neurology 71:140214092008

  • 34

    Hadjigeorgiou GMXiromerisiou GGourbali VAggelakis KScarmeas NPapadimitriou A: Association of alphasynuclein Rep1 polymorphism and Parkinson's disease: influence of Rep1 on age at onset. Mov Disord 21:5345392006

  • 35

    Hasegawa TTreis APatenge NFiesel FCSpringer WKahle PJ: Parkin protects against tyrosinase-mediated dopamine neurotoxicity by suppressing stress-activated protein kinase pathways. J Neurochem 105:170017152008

  • 36

    Hattersley ATMcCarthy MI: What makes a good genetic association study?. Lancet 366:131513232005

  • 37

    Healy DGFalchi MO'Sullivan SSBonifati VDurr ABressman S: Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol 7:5835902008

  • 38

    Herzog JVolkmann JKrack PKopper FPötter MLorenz D: Two-year follow-up of subthalamic deep brain stimulation in Parkinson's disease. Mov Disord 18:133213372003

  • 39

    Ito GOkai TFujino GTakeda KIchijo HKatada T: GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease. Biochemistry 46:138013882007

  • 40

    Kitada TAsakawa SHattori NMatsumine HYamamura YMinoshima S: Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:6056081998

  • 41

    Kleiner-Fisman GFisman DNSime ESaint-Cyr JALozano AMLang AE: Long-term follow up of bilateral deep brain stimulation of the subthalamic nucleus in patients with advanced Parkinson disease. J Neurosurg 99:4894952003

  • 42

    Krüger RKuhn WMüller TWoitalla DGraeber MKösel S: Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet 18:1061081998

  • 43

    Lai BCMarion SATeschke KTsui JK: Occupational and environmental risk factors for Parkinson's disease. Parkinsonism Relat Disord 8:2973092002

  • 44

    Langston JWBallard PTetrud JWIrwin I: Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:9799801983

  • 45

    Lesage SDürr ATazir MLohmann ELeutenegger ALJanin S: LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. N Engl J Med 354:4224232006

  • 46

    Lesage SJanin SLohmann ELeutenegger ALLeclere LViallet F: LRRK2 exon 41 mutations in sporadic Parkinson disease in Europeans. Arch Neurol 64:4254302007

  • 47

    Lesnick TGPapapetropoulos SMash DCFfrench-Mullen JShehadeh Lde Andrade M: A genomic pathway approach to a complex disease: axon guidance and Parkinson disease. PLoS Genet 3:e982007

  • 48

    Lesnick TGSorenson EJAhlskog JEHenley JRShehadeh LPapapetropoulos S: Beyond Parkinson disease: amyotrophic lateral sclerosis and the axon guidance pathway. PLoS One 3:e14492008

  • 49

    Li YRowland CXiromerisiou GLagier RJSchrodi SJDradiotis E: Neither replication nor simulation supports a role for the axon guidance pathway in the genetics of Parkinson's disease. PLoS One 3:e27072008

  • 50

    Lloyd-Evans EPelled DRiebeling CBodennec Jde-Morgan AWaller H: Glucosylceramide and glucosylsphingosine modulate calcium mobilization from brain microsomes via different mechanisms. J Biol Chem 278:23594235992003

  • 51

    Lohmann EWelter MLFraix VKrack PLesage SLaine S: Are parkin patients particularly suited for deep-brain stimulation?. Mov Disord 23:7407432008

  • 52

    Machado ARezai ARKopell BHGross RESharan ADBenabid AL: Deep brain stimulation for Parkinson's disease: surgical technique and perioperative management. Mov Disord 21 Suppl 14:S247S2582006

  • 53

    Maraganore DMde Andrade MElbaz AFarrer MJIoannidis JPKrüger R: Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 296:6616702006

  • 54

    Maraganore DMde Andrade MLesnick TGStrain KJFarrer MJRocca WA: High-resolution whole-genome association study of Parkinson disease. Am J Hum Genet 77:6856932005

  • 55

    Maraganore DMLesnick TGElbaz AChartier-Harlin MCGasser TKrüger R: UCHL1 is a Parkinson's disease susceptibility gene. Ann Neurol 55:5125212004

  • 56

    Massey ACKaushik SSovak GKiffin RCuervo AM: Consequences of the selective blockage of chaperone-mediated autophagy. Proc Natl Acad Sci U S A 103:580558102006

  • 57

    Mata IFSamii ASchneer SHRoberts JWGriffith ALeis BC: Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Arch Neurol 65:3793822008

  • 58

    Mata IFWedemeyer WJFarrer MJTaylor JPGallo KA: LRRK2 in Parkinson's disease: protein domains and functional insights. Trends Neurosci 29:2862932006

  • 59

    Mitsui JMizuta IToyoda AAshida RTakahashi YGoto J: Mutations for Gaucher disease confer high susceptibility to Parkinson disease. Arch Neurol 66:5715762009

  • 60

    Mizuta ISatake WNakabayashi YIto CSuzuki SMomose Y: Multiple candidate gene analysis identifies alpha-synuclein as a susceptibility gene for sporadic Parkinson's disease. Hum Mol Genet 15:115111582006

  • 61

    Nosaka CKunimoto SAtsumi STakeuchi T: Inhibition of nitric oxide synthase induction by 15-deoxyspergualin in a cultured macrophage cell line, J774A.1 [correction of J744A.1] activated with IFN-gamma and LPS. J Antibiot (Tokyo) 52:2973041999

  • 62

    Ozelius LJSenthil GSaunders-Pullman ROhmann EDeligtisch ATagliati M: LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N Engl J Med 354:4244252006

  • 63

    Paisán-Ruíz CJain SEvans EWGilks WPSimón Jvan der Brug M: Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44:5956002004

  • 64

    Pals PLincoln SManning JHeckman MSkipper LHulihan M: α-Synuclein promoter confers susceptibility to Parkinson's disease. Ann Neurol 56:5915952004

  • 65

    Papadimitriou AVeletza VHadjigeorgiou GMPatrikiou AHirano MAnastasopoulos I: Mutated alpha-synuclein gene in two Greek kindreds with familial PD: incomplete penetrance?. Neurology 52:6516541999

  • 66

    Peppe APierantozzi MBassi AAltibrandi MGBrusa LStefani A: Stimulation of the subthalamic nucleus compared with the globus pallidus internus in patients with Parkinson disease. J Neurosurg 101:1952002004

  • 67

    Polymeropoulos MHLavedan CLeroy EIde SEDehejia ADutra A: Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276:204520471997

  • 68

    Portman ATGiladi NLeenders KLMaguire PVeenma-van der Duin LSwart J: The nigrostriatal dopaminergic system in familial early onset parkinsonism with parkin mutations. Neurology 56:175917622001

  • 69

    Pridgeon JWOlzmann JAChin LSLi L: PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol 5:e1722007

  • 70

    Priyadarshi AKhuder SASchaub EAShrivastava S: A meta-analysis of Parkinson's disease and exposure to pesticides. Neurotoxicology 21:4354402000

  • 71

    Ramirez AHeimbach AGründemann JStiller BHampshire DCid LP: Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 38:118411912006

  • 72

    Ricciuti RAAgostini EIacoangeli MRychlicki FCapecci MGabriella MG: [Deep brain stimulation in Parkinson's disease. Experience in Ancona.]. J Neurosurg Sci 47:1 Suppl 112162003. (Ital)

  • 73

    Romito LMContarino MFGhezzi DFranzini AGaravaglia BAlbanese A: High frequency stimulation of the subthalamic nucleus is efficacious in Parkin disease. J Neurol 252:2082112005

  • 74

    Saint-Cyr JATrépanier LLKumar RLozano AMLang AE: Neuropsychological consequences of chronic bilateral stimulation of the subthalamic nucleus in Parkinson's disease. Brain 123:Pt 10209121082000

  • 75

    Schüpbach MLohmann EAnheim MLesage SCzernecki VYaici S: Subthalamic nucleus stimulation is efficacious in patients with Parkinsonism and LRRK2 mutations. Mov Disord 22:1191222007

  • 76

    Singleton ABFarrer MJohnson JSingleton AHague SKachergus J: α-Synuclein locus triplication causes Parkinson's disease. Science 302:8412003

  • 77

    Spira PJSharpe DMHalliday GCavanagh JNicholson GA: Clinical and pathological features of a Parkinsonian syndrome in a family with an Ala53Thr alpha-synuclein mutation. Ann Neurol 49:3133192001

  • 78

    Tan EKKhajavi MThornby JINagamitsu SJankovic JAshizawa T: Variability and validity of polymorphism association studies in Parkinson's disease. Neurology 55:5335382000

  • 79

    Tan EKPuong KYFook-Chong SChua EShen HYuen Y: Case-control study of UCHL1 S18Y variant in Parkinson's disease. Mov Disord 21:176517682006

  • 80

    Tan EKZhao YSkipper LTan MGDi Fonzo ASun L: The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: genetic and functional evidence. Hum Genet 120:8578632007

  • 81

    Valente EMAbou-Sleiman PMCaputo VMuqit MMHarvey KGispert S: Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304:115811602004

  • 82

    Valente EMSalvi SIalongo TMarongiu RElia AECaputo V: PINK1 mutations are associated with sporadic earlyonset parkinsonism. Ann Neurol 56:3363412004

  • 83

    van de Warrenburg BPLammens MLücking CBDenèfle PWesseling PBooij J: Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations. Neurology 56:5555572001

  • 84

    Volles MJLansbury PT Jr: Zeroing in on the pathogenic form of alpha-synuclein and its mechanism of neurotoxicity in Parkinson's disease. Biochemistry 42:787178782003

  • 85

    West ABMoore DJChoi CAndrabi SALi XDikeman D: Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum Mol Genet 16:2232322007

  • 86

    Winkler SHagenah JLincoln SHeckman MHaugarvoll KLohmann-Hedrich K: α-Synuclein and Parkinson disease susceptibility. Neurology 69:174517502007

  • 87

    Wintermeyer PKrüger RKuhn WMüller TWoitalla DBerg D: Mutation analysis and association studies of the UCHL1 gene in German Parkinson's disease patients. Neuroreport 11:207920822000

  • 88

    Wong KSidransky EVerma AMixon TSandberg GDWakefield LK: Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol Genet Metab 82:1922072004

  • 89

    Wood-Kaczmar AGandhi SWood NW: Understanding the molecular causes of Parkinson's disease. Trends Mol Med 12:5215282006

  • 90

    Xiromerisiou GHadjigeorgiou GMGourbali VJohnson JPapakonstantinou IPapadimitriou A: Screening for SNCA and LRRK2 mutations in Greek sporadic and autosomal dominant Parkinson's disease: identification of two novel LRRK2 variants. Eur J Neurol 14:7112007

  • 91

    Yang YGehrke SImai YHuang ZOuyang YWang JW: Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proc Natl Acad Sci U S A 103:10793107982006

  • 92

    Zarranz JJAlegre JGómez-Esteban JCLezcano ERos RAmpuero I: The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:1641732004

  • 93

    Zhang LShimoji MThomas BMoore DJYu SWMarupudi NI: Mitochondrial localization of the Parkinson's disease related protein DJ-1: implications for pathogenesis. Hum Mol Genet 14:206320732005

  • 94

    Zimprich ABiskup SLeitner PLichtner PFarrer MLincoln S: Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:6016072004

  • 95

    Zorzon MCapus LPellegrino ACazzato GZivadinov R: Familial and environmental risk factors in Parkinson's disease: a case-control study in north-east Italy. Acta Neurol Scand 105:77822002

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Article Information

Address correspondence to: Georgios Hadjigeorgiou, M.D., Laboratory of Neurogenetics, Department of Neurology, School of Medicine, University of Thessaly, 22 Papakyriazi Street, GR-41222 Larissa, Greece. email: gmhadji@med.uth.gr.

© AANS, except where prohibited by US copyright law.

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References

1

Abbas NLücking CBRicard SDürr ABonifati VDe Michele G: A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. Hum Mol Genet 8:5675741999

2

Abou-Sleiman PMMuqit MMWood NW: Expanding insights of mitochondrial dysfunction in Parkinson's disease. Nat Rev Neurosci 7:2072192006

3

Albanese AValente EMRomito LMBellacchio EElia AEDallapiccola B: The PINK1 phenotype can be indistinguishable from idiopathic Parkinson disease. Neurology 64:195819602005

4

Berg DSchweitzer KLeitner PZimprich ALichtner PBelcredi P: Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson's disease*. Brain 128:300030112005

5

Betarbet RSherer TBGreenamyre JT: Ubiquitin-proteasome system and Parkinson's diseases. Exp Neurol 191:Suppl 1S17S272005

6

Bonifati VRizzu Pvan Baren MJSchaap OBreedveld GJKrieger E: Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:2562592003

7

Canet-Avilés RMWilson MAMiller DWAhmad RMcLendon CBandyopadhyay S: The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic aciddriven mitochondrial localization. Proc Natl Acad Sci U S A 101:910391082004

8

Capecci MPassamonti LAnnesi FAnnesi GBellesi MCandiano IC: Chronic bilateral subthalamic deep brain stimulation in a patient with homozygous deletion in the parkin gene. Mov Disord 19:145014522004

9

Charles PDVan Blercom NKrack PLee SLXie JBesson G: Predictors of effective bilateral subthalamic nucleus stimulation for PD. Neurology 59:9329342002

10

Chartier-Harlin MCKachergus JRoumier CMouroux VDouay XLincoln S: Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364:116711692004

11

Chiba-Falek ONussbaum RL: Effect of allelic variation at the NACP-Rep1 repeat upstream of the alpha-synuclein gene (SNCA) on transcription in a cell culture luciferase reporter system. Hum Mol Genet 10:310131092001

12

Cookson MRXiromerisiou GSingleton A: How genetics research in Parkinson's disease is enhancing understanding of the common idiopathic forms of the disease. Curr Opin Neurol 18:7067112005

13

Cuervo AMStefanis LFredenburg RLansbury PTSulzer D: Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305:129212952004

14

Di Fonzo ADekker MCMontagna PBaruzzi AYonova EHCorreia Guedes L: FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome. Neurology 72:2402452009

15

Di Fonzo AWu-Chou YHLu CSvan Doeselaar MSimons EJRohé CF: A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson's disease risk in Taiwan. Neurogenetics 7:1331382006

16

Elbaz ANelson LMPayami HIoannidis JPFiske BKAnnesi G: Lack of replication of thirteen single-nucleotide polymorphisms implicated in Parkinson's disease: a large-scale international study. Lancet Neurol 5:9179232006

17

Ephraty LPorat OIsraeli DCohen OSTunkel OYael S: Neuropsychiatric and cognitive features in autosomal-recessive early parkinsonism due to PINK1 mutations. Mov Disord 22:5665692007

18

Eriksen JLPrzedborski SPetrucelli L: Gene dosage and pathogenesis of Parkinson's disease. Trends Mol Med 11:91962005

19

Evangelou EMaraganore DMAnnesi GBrighina LBrice AElbaz A: Non-replication of association for six polymorphisms from meta-analysis of genome-wide association studies of Parkinson's disease: large-scale collaborative study. Am J Med Genet B Neuropsychiatr Genet [epub ahead of print]2009

20

Evangelou EMaraganore DMIoannidis JP: Meta-analysis in genome-wide association datasets: strategies and application in Parkinson disease. PLoS One 2:e1962007

21

Farrer MJStone JTLin CHDächsel JCHulihan MMHaugarvoll K: Lrrk2 G2385R is an ancestral risk factor for Parkinson's disease in Asia. Parkinsonism Relat Disord 13:89922007

22

Firestone JASmith-Weller TFranklin GSwanson PLongstreth WT JrCheckoway H: Pesticides and risk of Parkinson disease: a population-based case-control study. Arch Neurol 62:91952005

23

Fuchs JNilsson CKachergus JMunz MLarsson EMSchüle B: Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication. Neurology 68:9169222007

24

Funayama MLi YTomiyama HYoshino HImamichi YYamamoto M: Leucine-rich repeat kinase 2 G2385R variant is a risk factor for Parkinson disease in Asian population. Neuroreport 18:2732752007

25

Fung HCScholz SMatarin MSimón-Sánchez JHernandez DBritton A: Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol 5:9119162006

26

Fung HCXiromerisiou GGibbs JRWu YREerola JGourbali V: Association of tau haplotype-tagging polymorphisms with Parkinson's disease in diverse ethnic Parkinson's disease cohorts. Neurodegener Dis 3:3273332006

27

Galpern WRLang AE: Interface between tauopathies and synucleinopathies: a tale of two proteins. Ann Neurol 59:4494582006

28

Gilks WPAbou-Sleiman PMGandhi SJain SSingleton ALees AJ: A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 365:4154162005

29

Goldberg MSLansbury PT Jr: Is there a cause-and-effect relationship between alpha-synuclein fibrillization and Parkinson's disease?. Nat Cell Biol 2:E115E1192000

30

Gómez-Esteban JCLezcano EZarranz JJGonzález CBilbao GLambarri I: Outcome of bilateral deep brain subthalamic stimulation in patients carrying the R1441G mutation in the LRRK2 dardarin gene. Neurosurgery 62:8578632008

31

Goris AWilliams-Gray CHClark GRFoltynie TLewis SJBrown J: Tau and alpha-synuclein in susceptibility to, and dementia in, Parkinson's disease. Ann Neurol 62:1451532007

32

Greggio EJain SKingsbury ABandopadhyay RLewis PKaganovich A: Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol Dis 23:3293412006

33

Gregory AWestaway SKHolm IEKotzbauer PTHogarth PSonek S: Neurodegeneration associated with genetic defects in phospholipase A(2). Neurology 71:140214092008

34

Hadjigeorgiou GMXiromerisiou GGourbali VAggelakis KScarmeas NPapadimitriou A: Association of alphasynuclein Rep1 polymorphism and Parkinson's disease: influence of Rep1 on age at onset. Mov Disord 21:5345392006

35

Hasegawa TTreis APatenge NFiesel FCSpringer WKahle PJ: Parkin protects against tyrosinase-mediated dopamine neurotoxicity by suppressing stress-activated protein kinase pathways. J Neurochem 105:170017152008

36

Hattersley ATMcCarthy MI: What makes a good genetic association study?. Lancet 366:131513232005

37

Healy DGFalchi MO'Sullivan SSBonifati VDurr ABressman S: Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol 7:5835902008

38

Herzog JVolkmann JKrack PKopper FPötter MLorenz D: Two-year follow-up of subthalamic deep brain stimulation in Parkinson's disease. Mov Disord 18:133213372003

39

Ito GOkai TFujino GTakeda KIchijo HKatada T: GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease. Biochemistry 46:138013882007

40

Kitada TAsakawa SHattori NMatsumine HYamamura YMinoshima S: Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:6056081998

41

Kleiner-Fisman GFisman DNSime ESaint-Cyr JALozano AMLang AE: Long-term follow up of bilateral deep brain stimulation of the subthalamic nucleus in patients with advanced Parkinson disease. J Neurosurg 99:4894952003

42

Krüger RKuhn WMüller TWoitalla DGraeber MKösel S: Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet 18:1061081998

43

Lai BCMarion SATeschke KTsui JK: Occupational and environmental risk factors for Parkinson's disease. Parkinsonism Relat Disord 8:2973092002

44

Langston JWBallard PTetrud JWIrwin I: Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:9799801983

45

Lesage SDürr ATazir MLohmann ELeutenegger ALJanin S: LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. N Engl J Med 354:4224232006

46

Lesage SJanin SLohmann ELeutenegger ALLeclere LViallet F: LRRK2 exon 41 mutations in sporadic Parkinson disease in Europeans. Arch Neurol 64:4254302007

47

Lesnick TGPapapetropoulos SMash DCFfrench-Mullen JShehadeh Lde Andrade M: A genomic pathway approach to a complex disease: axon guidance and Parkinson disease. PLoS Genet 3:e982007

48

Lesnick TGSorenson EJAhlskog JEHenley JRShehadeh LPapapetropoulos S: Beyond Parkinson disease: amyotrophic lateral sclerosis and the axon guidance pathway. PLoS One 3:e14492008

49

Li YRowland CXiromerisiou GLagier RJSchrodi SJDradiotis E: Neither replication nor simulation supports a role for the axon guidance pathway in the genetics of Parkinson's disease. PLoS One 3:e27072008

50

Lloyd-Evans EPelled DRiebeling CBodennec Jde-Morgan AWaller H: Glucosylceramide and glucosylsphingosine modulate calcium mobilization from brain microsomes via different mechanisms. J Biol Chem 278:23594235992003

51

Lohmann EWelter MLFraix VKrack PLesage SLaine S: Are parkin patients particularly suited for deep-brain stimulation?. Mov Disord 23:7407432008

52

Machado ARezai ARKopell BHGross RESharan ADBenabid AL: Deep brain stimulation for Parkinson's disease: surgical technique and perioperative management. Mov Disord 21 Suppl 14:S247S2582006

53

Maraganore DMde Andrade MElbaz AFarrer MJIoannidis JPKrüger R: Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 296:6616702006

54

Maraganore DMde Andrade MLesnick TGStrain KJFarrer MJRocca WA: High-resolution whole-genome association study of Parkinson disease. Am J Hum Genet 77:6856932005

55

Maraganore DMLesnick TGElbaz AChartier-Harlin MCGasser TKrüger R: UCHL1 is a Parkinson's disease susceptibility gene. Ann Neurol 55:5125212004

56

Massey ACKaushik SSovak GKiffin RCuervo AM: Consequences of the selective blockage of chaperone-mediated autophagy. Proc Natl Acad Sci U S A 103:580558102006

57

Mata IFSamii ASchneer SHRoberts JWGriffith ALeis BC: Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Arch Neurol 65:3793822008

58

Mata IFWedemeyer WJFarrer MJTaylor JPGallo KA: LRRK2 in Parkinson's disease: protein domains and functional insights. Trends Neurosci 29:2862932006

59

Mitsui JMizuta IToyoda AAshida RTakahashi YGoto J: Mutations for Gaucher disease confer high susceptibility to Parkinson disease. Arch Neurol 66:5715762009

60

Mizuta ISatake WNakabayashi YIto CSuzuki SMomose Y: Multiple candidate gene analysis identifies alpha-synuclein as a susceptibility gene for sporadic Parkinson's disease. Hum Mol Genet 15:115111582006

61

Nosaka CKunimoto SAtsumi STakeuchi T: Inhibition of nitric oxide synthase induction by 15-deoxyspergualin in a cultured macrophage cell line, J774A.1 [correction of J744A.1] activated with IFN-gamma and LPS. J Antibiot (Tokyo) 52:2973041999

62

Ozelius LJSenthil GSaunders-Pullman ROhmann EDeligtisch ATagliati M: LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N Engl J Med 354:4244252006

63

Paisán-Ruíz CJain SEvans EWGilks WPSimón Jvan der Brug M: Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44:5956002004

64

Pals PLincoln SManning JHeckman MSkipper LHulihan M: α-Synuclein promoter confers susceptibility to Parkinson's disease. Ann Neurol 56:5915952004

65

Papadimitriou AVeletza VHadjigeorgiou GMPatrikiou AHirano MAnastasopoulos I: Mutated alpha-synuclein gene in two Greek kindreds with familial PD: incomplete penetrance?. Neurology 52:6516541999

66

Peppe APierantozzi MBassi AAltibrandi MGBrusa LStefani A: Stimulation of the subthalamic nucleus compared with the globus pallidus internus in patients with Parkinson disease. J Neurosurg 101:1952002004

67

Polymeropoulos MHLavedan CLeroy EIde SEDehejia ADutra A: Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276:204520471997

68

Portman ATGiladi NLeenders KLMaguire PVeenma-van der Duin LSwart J: The nigrostriatal dopaminergic system in familial early onset parkinsonism with parkin mutations. Neurology 56:175917622001

69

Pridgeon JWOlzmann JAChin LSLi L: PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol 5:e1722007

70

Priyadarshi AKhuder SASchaub EAShrivastava S: A meta-analysis of Parkinson's disease and exposure to pesticides. Neurotoxicology 21:4354402000

71

Ramirez AHeimbach AGründemann JStiller BHampshire DCid LP: Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 38:118411912006

72

Ricciuti RAAgostini EIacoangeli MRychlicki FCapecci MGabriella MG: [Deep brain stimulation in Parkinson's disease. Experience in Ancona.]. J Neurosurg Sci 47:1 Suppl 112162003. (Ital)

73

Romito LMContarino MFGhezzi DFranzini AGaravaglia BAlbanese A: High frequency stimulation of the subthalamic nucleus is efficacious in Parkin disease. J Neurol 252:2082112005

74

Saint-Cyr JATrépanier LLKumar RLozano AMLang AE: Neuropsychological consequences of chronic bilateral stimulation of the subthalamic nucleus in Parkinson's disease. Brain 123:Pt 10209121082000

75

Schüpbach MLohmann EAnheim MLesage SCzernecki VYaici S: Subthalamic nucleus stimulation is efficacious in patients with Parkinsonism and LRRK2 mutations. Mov Disord 22:1191222007

76

Singleton ABFarrer MJohnson JSingleton AHague SKachergus J: α-Synuclein locus triplication causes Parkinson's disease. Science 302:8412003

77

Spira PJSharpe DMHalliday GCavanagh JNicholson GA: Clinical and pathological features of a Parkinsonian syndrome in a family with an Ala53Thr alpha-synuclein mutation. Ann Neurol 49:3133192001

78

Tan EKKhajavi MThornby JINagamitsu SJankovic JAshizawa T: Variability and validity of polymorphism association studies in Parkinson's disease. Neurology 55:5335382000

79

Tan EKPuong KYFook-Chong SChua EShen HYuen Y: Case-control study of UCHL1 S18Y variant in Parkinson's disease. Mov Disord 21:176517682006

80

Tan EKZhao YSkipper LTan MGDi Fonzo ASun L: The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: genetic and functional evidence. Hum Genet 120:8578632007

81

Valente EMAbou-Sleiman PMCaputo VMuqit MMHarvey KGispert S: Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304:115811602004

82

Valente EMSalvi SIalongo TMarongiu RElia AECaputo V: PINK1 mutations are associated with sporadic earlyonset parkinsonism. Ann Neurol 56:3363412004

83

van de Warrenburg BPLammens MLücking CBDenèfle PWesseling PBooij J: Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations. Neurology 56:5555572001

84

Volles MJLansbury PT Jr: Zeroing in on the pathogenic form of alpha-synuclein and its mechanism of neurotoxicity in Parkinson's disease. Biochemistry 42:787178782003

85

West ABMoore DJChoi CAndrabi SALi XDikeman D: Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum Mol Genet 16:2232322007

86

Winkler SHagenah JLincoln SHeckman MHaugarvoll KLohmann-Hedrich K: α-Synuclein and Parkinson disease susceptibility. Neurology 69:174517502007

87

Wintermeyer PKrüger RKuhn WMüller TWoitalla DBerg D: Mutation analysis and association studies of the UCHL1 gene in German Parkinson's disease patients. Neuroreport 11:207920822000

88

Wong KSidransky EVerma AMixon TSandberg GDWakefield LK: Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol Genet Metab 82:1922072004

89

Wood-Kaczmar AGandhi SWood NW: Understanding the molecular causes of Parkinson's disease. Trends Mol Med 12:5215282006

90

Xiromerisiou GHadjigeorgiou GMGourbali VJohnson JPapakonstantinou IPapadimitriou A: Screening for SNCA and LRRK2 mutations in Greek sporadic and autosomal dominant Parkinson's disease: identification of two novel LRRK2 variants. Eur J Neurol 14:7112007

91

Yang YGehrke SImai YHuang ZOuyang YWang JW: Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proc Natl Acad Sci U S A 103:10793107982006

92

Zarranz JJAlegre JGómez-Esteban JCLezcano ERos RAmpuero I: The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:1641732004

93

Zhang LShimoji MThomas BMoore DJYu SWMarupudi NI: Mitochondrial localization of the Parkinson's disease related protein DJ-1: implications for pathogenesis. Hum Mol Genet 14:206320732005

94

Zimprich ABiskup SLeitner PLichtner PFarrer MLincoln S: Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:6016072004

95

Zorzon MCapus LPellegrino ACazzato GZivadinov R: Familial and environmental risk factors in Parkinson's disease: a case-control study in north-east Italy. Acta Neurol Scand 105:77822002

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