Genetics of Parkinson’s Disease — Volkswagen Santana Variant II

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Genetics of Parkinson#x02019;s Disease

Fifteen years of genetic in Parkinson#x02019;s disease (PD) led to the identification of several monogenic of the disorder and of numerous genetic factors increasing the risk to PD. Monogenic forms, caused by a mutation in a dominantly or recessively gene, are well-established, albeit rare types of PD. They account for about 30% of the familial and of the sporadic cases. In this we will summarize the current and understanding of the molecular genetics of PD. In we will review familial of PD, basic genetic principles of (and their exceptions in followed by current methods for the of PD genes and risk factors, and for genetic testing.

In 1996, the and subsequent identification of the first responsible for Parkinson#x02019;s disease indisputably showed that PD may be (Polymeropoulos et al. 1996. 1997 ). In the two to follow, genetic links of PD to two new regions were reported, and to the first gene was excluded in a number of families (Munoz et al. ; Scott et al. 1997. 1999 ; et al. 1998 ). Thus, it became that PD is a genetically heterogeneous and likely, complex disorder.

how complex it is, is underlined by the notion today, nearly 15 years we know of 28 distinct chromosomal more or less convincingly to PD. Only six of these specific contain genes with that conclusively cause PD; that is, a form of the disease for a mutation in a single gene is to cause the phenotype. Even mutations in these six genes only a limited number of sporadic disease occurrences. the etiology of PD is multifactorial, which results from an elaborate of mostly unknown factors: genes, modifying effects by alleles, environmental exposures and interactions (e.g. influence of agents on gene expression), and direct impact on the developing and brain.

In this article, we summarize the current knowledge and of the molecular genetics of PD and outline its principles. First, we will the present genetic #x0201c;classification#x0201d; of PD and some of the existing inconsistences Second, we will explain genetic principles of inheritance of disorders and will define the that a researcher trying to the inheritance pattern of PD in a particular needs to be aware of. Third, we describe state-of-the-art methods for the of new PD genes and risk factors. we will cover the most genes contributing to the pathogenesis of PD and which patients should be for diagnostic genetic testing.


In the current PD genetics 18 specific chromosomal regions, called chromosomal locus, are PARK (to denote their link to PD), and numbered in order of their identification ( . PARK2 . PARK3 . etc.) ( ). In addition to being an incomplete of known PD-related genes, classification system, unfortunately, has a of inconsistencies. It comprises confirmed as well as those for which or association could not be replicated The causative gene has not yet been for all of the loci, nor do all of the identified genes causative or disease-determining mutations variations in some of these are considered genetic risk increasing the risk to develop PD than being a sufficient Finally, one locus, PARK4 . was as a novel chromosomal region with PD (Farrer et al. 1999 ; et al. 2003 ) but was later found to be with PARK1 ( SNCA PD) (Singleton et al. 2003 ). It is noteworthy some of the loci have identified by genetic linkage in large families, some on the known function of the protein of the gene they contain, yet have been established by association studies performed on a level. A list of the PARK genes and loci is given in along with their classification, inheritance pattern applicable), gene (when status (confirmed/nonconfirmed), and mode of

PARK -designated PD-related


The majority of PD cases are i.e. only about 10% of report a positive family (Thomas and Beal 2007 ). Out of the six unequivocally linked to heritable, PD, mutations in SNCA ( PARK 1 = 4), and ( PARK8 ) are responsible for autosomal-dominant PD and mutations in Parkin ( PARK2 ), ( PARK6 ), DJ-1 ( PARK7 ), and ( PARK9 ) are accountable for PD that an autosomal recessive (AR) of inheritance.

In autosomal-dominant disorders, one mutated of the gene is enough to cause the Thus, defining features in a family tree with an inheritance pattern are (1) every person in the pedigree must at least one affected parent, (2) at one affected individual is present in generation, and (3) on average, an affected will transmit the mutant to half of his or her children ( Fig.#x000a0;1 A). In AR two mutations (the same#x02014;homozygous, or one on each gene copy are necessary to cause the phenotype. mutation carriers (individuals a pathogenic mutation only on one are phenotypically normal, i.e. A clear AR mode of inheritance has determining characteristics: (1) affected members have two unaffected both of whom are heterozygous, (2) of the affected individual are also and heterozygous, and (3) as both of the affected parents are expected to be heterozygous of the mutated gene, only one in children (25%) is affected ( B). Thus, the most striking between these two types of is that in AR, a #x0201c;generation skipping#x0201d; is Of note, in autosomal-linked pedigrees, the of affected males and females is equal, whereas families an unequal representation of affected men and can imply a … chromosome-linked pattern.

Pedigrees showing inheritance patterns. ( A ) Autosomal disease inheritance pattern. affected person in the pedigree has one parent, one affected individual is in every generation, and on average, an individual .

Pedigree of a PD family comprises affected members and without the LRRK2 p.G2019S Five mutation carriers are showing reduced penetrance, two carriers are affected with showing variable expressivity, and .

In reduced penetrance, variable affected single heterozygous carriers, and phenocopies pose when trying to decide if a has a positive family history of PD, or trying to determine which or genetic-testing method to use. to incomplete penetrance, autosomal-dominant may seem to #x0201c;skip generations,#x0201d; and they might be falsely as AR. In addition, because of a very or even clinically distinct resulting from the variable some mutation carriers be misdiagnosed and not considered affected by the disease. Also, some classified as affected by the same as patients in the rest of the family, may not carry the (same) disease-causing Finally, some patients by an AR form of disease and carrying a single heterozygous mutation may the pedigree to erroneously look dominant.


New PD-linked genes or PD factors can be identified by gene or candidate gene approaches. mapping in human diseases is the of genes underlying the clinical of the disease on the basis of correlation DNA variants (polymorphic markers), the need for prior hypotheses biological function. Genetic methods include linkage and genome-wide association studies. based on their known levels of expression, or mode of (candidate gene approach), genes can be considered plausible and as such, tested for in cohorts of

The gene underlying any heritable of human disease can be mapped and by linkage analysis if the DNA samples a sufficient number of affected and family members are available. The step in classical linkage is to hypothesize the mode of inheritance of the on the basis of a constructed pedigree. this is frequently complicated by penetrance and other phenomena in the previous section. Linkage is based on the tendency of a disease-causing change and markers at specified to be inherited together (#x0201c;linked#x0201d;) as a of their physical proximity on a chromosome. The measure of the likelihood the disease-associated gene and any single are genetically linked rather unlinked is called the lod (the of the odds) score. A table of lod represents the result of a linkage for a Mendelian trait, with a lod #x0003e; +3 considered evidence of whereas one that is #x0003c;#x02212;2 evidence against linkage. the linked region is narrowed to the possible interval, sequencing of the in the region follows. The advent of sequencing technology, most next-generation sequencing (whole or whole exome, i.e. the part of the genome) facilitates identification. It is now possible to obtain the sequence of a patient#x02019;s genome in a and cost-efficient manner and to compare it to the genome. However, analysis of large amounts of data is not an task and it is often difficult to identify the disease-causing change and its pathogenicity among thousands of variants. Importantly, each differs from the current genome by putative loss-of-function in 250#x02013;300 genes (Durbin et al. ).

Genome-wide association studies represent another example of how a idea used in a novel, considerably upgraded setting can the discovery of genes associated human disorders. In GWAS, the of genetic risk factors for the of PD is achieved by analyzing as many as different single-nucleotide polymorphisms in large groups of sporadic PD (a few thousands) and healthy individuals, and SNP frequencies in the two groups. If certain are more frequent in PD patients, are considered to be #x0201c;associated#x0201d; with the These genetic variants are to indicate the region of the human where the PD-causing change is to be situated. Unlike GWAS, gene-association studies are based on the that a particular gene may be with PD owing to its function and to find this association. GWAS are mainly hypothesis-free, in days many PD risk (some also classified as s) have been identified in way but only a few of them could be replicated in independent studies.


SNCA (PARK1#x02013;4)

was the first gene with reported to cause autosomal-dominant PD. with SNCA mutations have early-onset PD (EOPD, age of #x02264;50 yr) with an initially response to levodopa treatment. the disease has a rapid progression and presents with dementia and decline, and sometimes with features such as central and myoclonus. Lewy bodies are and spread through the substantia locus ceruleus, hypothalamus, and cortex (Polymeropoulos et al. 1996 ).

mutations in SNCA are overall and thus far, only different missense mutations as as duplications and triplications of the entire have been reported and Schlossmacher 2006 ). Out of the three mutations, the first identified, seems to be by far the most frequent one and was in one Italian, eight Greek, two and one Swedish family (Polymeropoulos et al. ; Athanassiadou et al. 1999 ; Spira et al. ; Ki et al. 2007 ; Choi et al. 2008 ; et al. 2009 ). The p.A30P and p.E46K were identified in one family (Kruger et al. 1998 ; Zarranz et al. ). Seventeen duplications of the entire region of SNCA have reported to date, 13 in PD families and in sporadic cases, in one of which it was that the mutation arose de (Chartier-Harlin et al. 2004 ; Ibanez et al. ; Nishioka et al. 2006 ; Fuchs et al. ; Ahn et al. 2008 ; Brueggemann et al. 2008 ; et al. 2008 ; Troiano et al. 2008 ; et al. 2008 ; Ibanez et al. 2009 ). of the SNCA gene were in three independent families et al. 2003 ; Farrer et al. 2004 ; et al. 2009 ). Interestingly, one of the families a triplication was a branch of one family a duplication.

Penetrance of the missense appears to be high and is suggested to be as as 85% for the p.A53T mutation (Polymeropoulos et al. ). However, penetrance of gene is reduced and estimated at 33% in one family a duplication (Nishioka et al. 2006 ). dependence of the clinical symptoms on dosage has been suggested an increased number of SNCA ( SNCA triplications vs. duplications) associated with an earlier more severe phenotype, and disease progression (Fuchs et al. ; Ross et al. 2008 ).

The SNCA has six exons encoding an abundant acid cytosolic protein, #x003b1;-synuclein consists of three (i) the amino-terminal region (amino 7#x02013;87) contains seven repeats, each 11 amino in length, and is partially overlapping (ii) a central hydrophobic (amino acids 61#x02013;95), and an acidic, negatively charged domain (amino acids Thus, all three missense impair the amino-terminal domain. natively unfolded, with no secondary structure, once it to the phospholipid membranes, through its repeats (amino acids #x003b1;-synuclein adopts structures in #x003b1;-helical character (Giasson et al. ). Interestingly, the three-point mutants to form stable #x003b2; and thus exacerbate the formation of oligomers, protofibrils, and fibrils et al. 2005 ). Therefore, it is believed the missense SNCA mutations PD through a toxic gain of (Bertoncini et al. 2005 ), and Lewy may represent the attempt to purge the of toxic damaged #x003b1;-synuclein and Feany 2005 ). Wild-type is selectively translocated into for degradation (Cuervo et al. 2004 ), and of the lysosomal enzyme #x003b2;-glucocerebrosidase, in which represent a well-validated factor for PD, modulate #x003b1;-synuclein (Manning-Bog et al. 2009 ). Very it has been shown that the effect of #x003b1;-synuclein and #x003b2;-glucocerebrosidase a positive feedback loop leads to accumulation of #x003b1;-synuclein et al. 2011 ). Functional loss of causes the accumulation of glucocerebroside, directly influences aggregation of by stabilizing oligomeric intermediates et al. 2011 ). In turn, #x003b1;-synuclein the lysososmal activity of #x003b2;-glucocerebrosidase, as in neurons and idiopathic PD brain et al. 2011 ).


Mutations in the gene are the most frequent cause of late-onset autosomal-dominant and PD, with a mutation frequency from 2% to 40% in different populations 2005 ; Lesage et al. 2006 ; et al. 2006 ). Clinically, LRRK2 PD usually shows mid-to-late and progresses slowly. Patients favorably to levodopa therapy, and is not common. Neuropathological findings are inconsistent, showing both body (and sometimes and ubiquitin-containing inclusions) pathology and nigral degeneration without bodies, with or without tangles (Giasson et al. 2006 ).

is a large gene that of 51 exons. It encodes the 2527-amino cytoplasmic protein leucine-rich kinase 2 (LRRK2) that of a leucine-rich repeat toward the terminus of the protein and a kinase toward the carboxyl terminus various conserved domains in There are more than 50 missense and nonsense mutations in LRRK2 to date (Nuytemans et al. ) and at least 16 of them (including the six mutations#x02014;p.R114C, p.R1441G, p.R1441H, p.G2019S, and p.I2020T) seem to be These pathogenic changes are in 10 exons, mostly encoding the region of the protein. By far the most and best-studied mutation is c.6055G (p.G2019S) that accounts for as as 40% of cases of Arab descent et al. 2006 ), about 20% of Ashkenazi patients (Ozelius et al. 2006 ), and of PD patients of European origin et al. 2006 ; Zabetian et al. 2006 ). three different founders been described for the p.G2019S and at least 29 patients have reported to carry the mutation in the state (Klein and Lohmann-Hedrich ). Owing to a founder effect, the is very frequent in Basques et al. 2006 ; Gorostidi et al. 2009 ) and in Japanese patients (Tomiyama et al. ). Whereas p.G2019S shows penetrance, sometimes estimated to be as low as the p.R1441 mutation is highly (95% at the age of 75 yr) (Haugarvoll et al. 2008 ).

The mechanism leading to PD caused by mutations is still uncertain. is a large protein with domains capable of protein#x02013;protein and thus it is plausible that in these domains would the LRRK2#x02019;s relationship with proteins, i.e. currently interactors with which it complexes or which it phosphorylates. In various mutations affect its activity as shown for the p.G2019S and mutants (MacLeod et al. 2006 ).


Parkin was the second PD gene and the first gene causing an AR form of the disorder. The usually starts in the third or decade of the patients#x02019; life, and is slowly progressive with an response to dopaminergic treatment. some of the Parkin -mutation have an onset even in and homozygous mutations in Parkin are the frequent cause of juvenile PD of onset #x02264;21 yr). The phenotype of Parkin- . PINK1- . and -linked PD is indistinguishable. Reported examinations indicate that the nigra shows neuronal and gliosis, however, it is frequently Lewy bodies.

A large and wide spectrum of Parkin have been detected, alterations of all 12 exons, across ethnic groups. Parkin are the most common known of EOPD, accounting for up to 77% of the familial with an age of onset #x0003c;30 yr et al. 2000 ), and for 10%#x02013;20% of EOPD in general (Klein and Lohmann-Hedrich ). To our knowledge, 887 exonic mutations been described to date, 147 different changes. About a (293/887) of all exonic mutations are changes, 13% (119/887) are small and 54% (475/887) are deletions or duplications of one or exons (A Gr#x000fc;newald and C Klein, in However, because methods for the of exon rearrangements used to be intensive and expensive in the first after the identification of Parkin . were frequently omitted. the number of exon rearrangements is even underestimated.

Parkin is the second largest in human genome and codes for a acid protein with a architecture. The Parkin protein as an E3 ubiquitin ligase in the process of a form of posttranslational modification conjugates ubiquitin protein(s) to residue(s) of target proteins, in turn determines their fate. The amino-terminal ubiquitin-like (UBL) of Parkin shares 62% with ubiquitin and plays an role in stabilizing the structure and the expression levels of Parkin. The domain consists of three (really interesting new-gene) (amino acids 145#x02013;215 237#x02013;292 [RING1], and 417#x02013;448 and one IBR (in-between-ring) domain (amino 327#x02013;378) and is responsible for the interaction the ubiquitination machinery.

About of the published changes affect the spanning exons 2#x02013;4 459/887) that codes for the UBL the linker region, and the very of the RING0 domain. Although the total number of mutations was in exon 3 (257/887), exon 1 is for the highest mutation density 2.4 mutations per bp (followed by exon 4 1.3 mutations per bp). In exon 2, the diversity of mutations was found, 27 different variations. A deletion of 3 is the most frequent mutation in the gene (88/887, reported in 17 studies). The second most change is the c.924C#x0003e;T single-nucleotide in exon 7 (RING1), which was 75 times in 13 different screens (A and C Klein, in prep.).

From the of 2004 until July screening results of 4841 mostly EOPD cases, published. Parkin mutations detected in about 8% of these. than half of all mutation-positive (55%, 207/378) carried a heterozygous change. Twenty-five (94/378) of them were and the remaining 20% (77/378) harbored a mutation (A Gr#x000fc;newald and C Klein, in


Mutations in the and tensin homolog ( PTEN ) induced putative kinase 1 ( ) gene are the second most cause of AR EOPD. The frequency of mutations is in the range of 1%#x02013;9%, considerable variation across ethnic groups (Healy et al. ; Rogaeva et al. 2004 ; Valente et al. ; Bonifati et al. 2005 ; Klein et al. ; Li et al. 2005 ).

Interestingly, in contrast to . the majority of PINK1 mutations are either missense or nonsense and, to date only families with whole-exon (exons 4#x02013;8 [Cazeneuve et al. ], 6#x02013;8 [Li et al. 2005 ], and 7 [Camargos et al. ]) and one with a heterozygous whole-gene have been reported et al. 2007 ). More than 60 missense and nonsense mutations found in #x0003e;170 patients, all 8 PINK1 exons at nearly frequencies (in each of the exons different mutations were The largest total number of was found in exon 7 (in #x0003e;50 and the most frequent mutation is Although only a quarter of the mutations are truncating (vs. 3/4 #x0003e;40% of the total number of carry this type of

PINK1 is a 581 amino acid expressed protein kinase. It of an amino-terminal 34 amino acid targeting motif, a conserved kinase domain (amino 156#x02013;509; exons 2#x02013;8), and a autoregulatory domain. Two-thirds of the mutations in PINK1 are loss-of-function affecting the kinase domain, the importance of PINK1#x02019;s enzymatic in the pathogenesis of PD. Interestingly, recent provided evidence that and Parkin function in a common for sensing and selectively eliminating mitochondria from the mitochondrial PINK1 is stabilized on mitochondria lower membrane potential, and as it recruits Parkin from the Once recruited to mitochondria, becomes enzymatically active and the autophagic clearance of mitochondria by i.e. mitophagy (Youle and 2011 ).

DJ-1 (PARK7)

is the third gene associated AR PD, and it is mutated in about 1%#x02013;2% of cases (Pankratz et al. 2006 ). that DJ-1 -linked PD to be rare, very few patients been reported in the literature. about 10 different point and exonic deletions have described, mostly in the homozygous or state. Given that the are so uncommon, there is not enough to draw any conclusion about the role of heterozygous mutations in gene.

The seven coding exons of the gene code for a 189-amino protein that is ubiquitously and functions as a cellular sensor of stress (Canet-Aviles et al. 2004 ; et al. 2005 ). The DJ-1 protein a dimeric structure under conditions (Macedo et al. 2003 ), and it that most of the disease-causing (p.L166P, p.E64D, p.M26I, and heterodimerize with wild-type (Takahashi-Niki et al. 2004 ). In addition, the proteins are frequently not properly unstable, and promptly degraded by the Thus, their neuroprotective and antioxidant activity are reduced and Daggett 2008 ; Malgieri and 2008 ).


and compound-heterozygous mutations in ATP13A2 been found to cause an AR form of PD named Kufor-Rakeb (Ramirez et al. 2006 ). This has juvenile onset with disease progression, accompanied by supranuclear gaze palsy, and signs.

ATP13A2 is a large comprised of 29 exons coding for an acid protein. The ATP13A2 is normally located in the lysososmal and it has 10 transmembrane domains and an ATPase (Ramirez et al. 2006 ). About 10 pathogenic mutations have found in the homozygous or compound-heterozygous directly or indirectly affecting domains. Most of the mutations truncated proteins that are and are retained in the endoplasmic reticulum and degraded by the proteasome. No exonic or deletions or multiplications of the entire have been found, to Several single heterozygous mutations are known, but their in PD pathogenicity is currently not clear.


from the genes causing the six forms of PD, changes in a large of additional genes were PD-causative and identified by linkage or a candidate gene approach. of these genes even a #x0201c; PARKI #x0201d; (UCHL1 [ PARK5 ], GYGYF2 [ ], OMI/HTRA2 [ PARK13 ], PLA2G6 [ ], and FBXO7 [ PARK15 ]). However, as in the Genetic Classification of PD section, the of some of these genes to PD is and not confirmed. Furthermore, mutations in PARKs (i) cause PD that is an or only a minor feature of a complex phenotype or (ii) are a rare cause of PD (responsible for a few PD occurrences). In addition, mutations in . NR4A2/Nurr1 . POLG . mortalin . and presenilin-associated rhomboid-like protein were considered pathogenic on the known function or expression/protein pattern of the proteins they Nevertheless, they too, are now as only a minor contributor to the of genetic PD if at all.


Variants in PARK -designated ( SNCA . . LRRK2 . PARK 16 . GAK ) and a few other ( MAPT . GBA . NAT2 . INOS2A . GAK . . and APOE ) have been with an increased risk of PD. Such risk factors were mostly identified on GWAS and functional candidate Interestingly, polymorphic length and SNP in SNCA have repeatedly shown to be among the most PD risk factors, closely by the occurrence of the p.G2385R and p.R1628P SNPs in the LRRK2 gene. In to SNCA and LRRK2 that can be both in monogenic disease and act as a factor, #x003b2;-glucocerebrosidase (GBA) special attention as a well-validated risk factor.

The GBA gene a lysosomal enzyme #x003b2;-glucocerebrosidase an important role in glycolipid Loss-of-function mutations in #x003b2;-glucocerebrosidase an accumulation of glucocerebroside that in a wide spectrum of symptoms the liver, blood, bone spleen, lungs, and the nervous known as Gaucher disease. disease is inherited autosomal and, to date, about 300 nonsense, and frame-shift disease-causing have been identified et al. 2008 ). Interestingly, GBA mutations been found to increase the of developing PD and are found in 8%#x02013;14% of diagnoses of PD (Goker-Alpan et al. 2004 ; et al. 2004 ; Eblan et al. 2005 ; 2006 ) and both homozygous and GBA mutations appear to predispose to parkinsonism (Sidransky 2006 ). In relatives of patients with disease carrying heterozygous GBA have an increased incidence of PD et al. 2004 ; Halperin et al. 2006 ).

In in a large collaborative effort, 16 from Europe, Americas, and analyzed selected GBA mutations in (14% Ashkenazi Jews) PD and nearly 5000 (8% Ashkenazi healthy controls without history of PD and sequenced the entire region in a subset of subjects et al. 2009 ). Mutant GBA alleles found in 19.6% of Ashkenazi and in 6.9% of non-Ashkenazi Jewish In addition, the percentage of mutations was times higher in patients in to controls. Age at onset was found to be among subjects with GBA than in those without GBA The recent findings summarized in the Forms of PD-SNCA ( PARK1 = 4 ) of this article shed on how GBA mutations increase the risk of PD.


The answer to the question of who be tested is not trivial. To date, no testing guidelines have developed by the Movement Disorder or any other PD alliance group. Out of all forms, mutations in LRRK2 . . and PINK1 are the most likely to be in clinical practice. In the following genetic testing might useful to minimize further workup, to clarify treatment and/or to assist with family planning: juvenile-onset PD of family history; early-onset PD atypical features and/or a family history of this or late-onset PD with a strong history of PD (Klein and Schlossmacher ). Guidelines published by the European of the Neurological Sciences recommend LRRK2 for mutations in Europeans dominant inheritance of PD, testing for the p.G2019S mutation in familial and cases of PD in specific populations, and of Parkin . PINK1 . and DJ-1 in aged #x0003c;35 yr with inherited PD (Harbo et al. 2009 ).

patients with early-onset PD are in favor of genetic testing to understand their disease and to informed life decisions et al. 2001 ). A frequent argument against genetic testing for PD is the outcome of such testing not affect patient management. We this notion should be reconsidered, as the identification of a PD gene in a patient with early-onset has an important impact that beyond a reduction in diagnostic Indeed, the identification of specific can provide information on prognosis and affect treatment choices in of PD that were initially to be psychogenic. One other pertinent relating to the debate surrounding testing is that various tests are performed for patients parkinsonism (and not questioned) do not alter how patients are treated, as repeated MRI and single-photon-emission computed to differentiate multiple system from idiopathic PD.

Despite the presented above, genetic for PD genes should not be recommended or out of academic curiosity. Testing always be offered in the framework of counseling and based on an informed made by the patient. Of note, testing involving, for example, for the p.G2019S mutation in LRRK2 is increasingly available and sought by patients or even healthy Therefore, neurologists will to be prepared for patients seeking counseling for a #x0201c;genetic diagnosis of or for healthy individuals having an risk#x0201d; to develop PD based on the of risk SNPs. Such testing should be strongly and only the advent of neuroprotective or therapies is likely to profoundly our current views on the utility of testing for PD.


forms of PD are overall rare but of importance for a better understanding of the of idiopathic PD. Owing to the clinical, and in cases, also pathological genetic PD serves as an excellent model for the much more idiopathic condition and enables the of at-risk individuals in the earliest, premotor phases of the disease. All forms can be tested for in the diagnostic however, no causative treatment have yet become available 15 years of genetic PD research. perspectives for the next decade the development of improved human models for drug screening and medicine, generation of animal that replicate the clinical and findings in humans more and finally, the development of cause-directed

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