Parkinson s disease: A genetic perspective

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1 MINIREVIEW Parkinson s disease: A genetic perspective Andrea C. Belin and Marie Westerlund Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden Keywords dopamine; Lewy body; linkage; mitochondria; mutation; PARK locus; striatum; substantia nigra; synuclein; ubiquitin proteasome pathway Correspondence A. C. Belin, Department of Neuroscience, Karolinska Institutet, Retzius väg 8, Stockholm, Sweden Fax: Tel: andrea.carmine.belin@ki.se (Received 23 October 2007, revised 21 December 2007, accepted 7 January 2008) doi: /j x Parkinson s disease (PD) is a common neurodegenerative disorder in the aging population, affecting more than 1% over the age of 65 years. Certain rare forms of the disease are monogenic, representing 5 10% of PD patients, but there is increasing evidence that multiple genetic risk factors are important also for common forms of PD. To date, 13 genetic loci, PARK1-13, have been suggested for rare forms of PD such as autosomal dominant and autosomal recessive PD. At six of these loci, genes have been identified and reported by several groups to carry mutations that are linked to affected family members. Genes in which mutations have been linked to familial PD have also been shown to be candidate genes for idiopathic forms of PD, as those same genes may also carry other mutations that merely increase the risk. Four of the PARK genes, SNCA at PARK1, UCH-L1 at PARK5, PINK1 at PARK6 and LRRK2 at PARK8, have been implicated in sporadic PD. There are indeed multiple genetic risk factors that combine in different ways to increase or decrease risk, and several of these need to be identified in order to begin unwinding the causative pathways leading to the different forms of PD. In this review, we present the molecular genetics of PD that are understood today, to help explain the pathways leading to neurodegeneration. Introduction Parkinson s disease (PD) is a major disease that cannot be predicted and for which there is no cure. It is a common neurodegenerative disorder in the aging population, affecting more than 1% over the age of 65 years [1]. The incidence is similar worldwide, and the prevalence increases in proportion to regional increases in population longevity. It has been suggested that PD is somewhat more common among men than among women. The clinical symptoms of PD include rigidity, bradykinesia, impaired balance, and tremor at rest. The disease is also characterized by dopamine neuron degeneration and depigmentation of the substantia nigra accompanied by neuron loss in the ventral tegmental area and locus coeruleus, but there is degeneration of other neurons as well. Another typical PD characteristic is the presence of intracellular proteinaceous inclusions called Lewy bodies (LBs) and Lewy neurites in the brainstem and cortical areas. Although there is relatively good knowledge about the pathology and pathophysiology of the disease, there is almost no understanding of the etiology of this intensely researched condition, except for certain rare forms in which genetic factors dominate, representing 5 10% of PD patients. In order to develop better ways of combating PD, or better still, preventing clinical symptoms altogether, one must decipher the causes of the disease, and in doing so, take into account that there are different forms of PD and that any given phenotype may result from different genotypes. Abbreviations HTRA2, HtrA serine peptidase 2; LB, Lewy body; LRRK2, leucine-rich repeat kinase 2; PD, Parkinson s disease; PINK1, PTEN-induced putative kinase 1; UCH-L1, ubiquitin C-terminal hydrolase L1. FEBS Journal 275 (2008) ª 2008 The Authors Journal compilation ª 2008 FEBS 1377

2 Genetics of Parkinson s disease A. C. Belin and M. Westerlund The two major possibilities for identifying genetic risk factors are linkage and candidate gene association studies. Linkage studies are most successful in disorders with Mendelian inheritance without any prior knowledge about biology or gene function, and require families with affected and nonaffected members. Linkage studies become difficult, if they are possible at all, when many genes are involved and in various combinations, resulting in the same phenotype, or if mutations in individual genes only increase risk modestly. Moreover, owing to the relatively high age of PD onset, retrospective studies are difficult, as relatives may no longer be alive and or patients may not recall PD symptoms in affected relatives. Together, these and other circumstances suggest that the role of genetic risk factors has been underestimated in the past. Association studies can be used to refine the information obtained by linkage studies and to search for diseasemediating genetic variants. The studies are used to search for correlations between genetic variants and trait differences in populations of unrelated cases and unaffected control individuals, but there are some limitations. Association studies are frequently reported as irreproducible, possibly due to variation in mutation frequencies between different populations or small sample sizes leading to underpowered studies. Another explanation might be that a locus found to be associated with disease in one ethnic population might be in linkage disequilibrium with a true disease-causing locus that is not linked in other populations where association has not been found. Even if the incidence of a disease is geographically rather uniform, the importance of different genetic risk factors could vary between different populations. Parkinson s disease was for long considered to be a nongenetic disorder of sporadic origin, but during the last decade genetic findings from different geographical areas strengthened the hypothesis that PD is an inherited disorder. One of the earliest findings was made by Polymeropoulos et al., who discovered an autosomal dominant inherited form of PD in an Italian family and were able to identify a first locus, named PARK1, that segregated with disease [2]. The discovery of PARK1 was then followed by identification of several other loci linked to the disease (Table 1). To date, 13 loci, PARK1 13, have been suggested for rare forms of PD such as autosomal dominant and autosomal recessive PD [1]. Recently, it has been shown that genes in which mutations have been linked to familial forms of PD are also candidate genes for idiopathic forms of the disease, as those genes may also carry other mutations that merely increase risk. At six of the PARK loci, genes have been identified and reported by several groups to carry mutations that are linked to Table 1. Genetic causes of Parkinson s disease. AD, autosomal dominant; AR, autosmal recessive; J, juvenile; EO, early onset. PARK loci Gene Chromosome Form of PD Mutations Origin PARK1 SNCA 4q21 AD A30P, E46K, A53T Greece and Italy PARK2 Parkin 6q25.2 q27 AR J Various mutations, exonic Japan deletions, duplications and triplication PARK3 Unknown 2p13 AD Europe PARK4 SNCA 4q21 AD Duplication and triplication Iowa PARK5 UCHL1 4p14 AD and I93M and S18Y Germany idiopathic PARK6 PINK1 1p35 p36 AR G309D, exonic deletions Italy PARK7 DJ-1 1p36 AR and EO Homozygous exon, deletion Europe L166P PARK8 LRRK2 12q12 AD and idiopathic R1441C G H, Y1699C G2019S I2020T G2385R Japan PARK9 ATP13A2 1p36 Kufor Rakeb syndrome and EO PD Loss-of-function mutations Jordan, Italy and Brazil PARK10 Unknown 1p32 Idiopathic Iceland PARK11 Unknown 2q36 q37 AD and idiopathic North America PARK12 Unknown X Familial North America PARK13 HTRA2 2p13 Idiopathic A141S G399S Germany 1378 FEBS Journal 275 (2008) ª 2008 The Authors Journal compilation ª 2008 FEBS

3 A. C. Belin and M. Westerlund Genetics of Parkinson s disease affected family members, and four of these loci have also been implicated in sporadic PD. PARK1 and PARK4 The first linkage study on PD was conducted by Polymeropoulos et al., who mapped the first PD locus to chromosome 4q21 and hence named it PARK1 [2]. A nonsynonymous mutation (A53T) was later identified in the a-synuclein gene (SNCA) in Greek Italian PD families with an autosomal dominant pattern of inheritance [3]. Although this mutation is only a rare cause of PD in these unrelated families, it highlighted the genetic variability in the disease. The discovery of the point mutation A53T in SNCA was subsequently followed by the identification of the A30P and E46K mutations in unrelated German and Spanish PD families [1]. The gene dose of SNCA appears to be critical in PD, as gene multiplications (a triplication was previously referred to as PARK4) have been found to cause PD in a large American family [1]. Families encompassing missense mutations or multiplications of SNCA also have features of diffuse cortical LB disease [1]. In addition to the missense mutations found in the gene, intronic variations and promoter polymorphisms have also been associated with sporadic PD in some studies, suggesting that regulation of gene transcriptional activity and mrna stability might play a role in a-synuclein-associated PD [4]. SNCA encodes the a-synuclein protein, for which the normal physiological function has not yet been determined; however, a-synuclein has a potential role in synaptic plasticity, vesicle dynamics, and learning [5]. It has also been shown in a number of studies that a-synuclein is abundantly expressed in the brain and that it forms a major filamentous component of LBs and Lewy neurites in PD [6]. PARK2 A mutation in the Parkin gene was found at the PARK2 locus, mapped to chromosome 6q25.2 q27, in Japanese families with an autosomal recessive form of PD with early onset [7]. Parkin is a ubiquitin E3 ligase responsible for the addition of ubiquitin to specific substrates, targeting them for degradation by the proteasome. The involvement of Parkin in the ubiquitin proteasome pathway strengthens the hypothesis that protein degradation and aggregation are central in the pathogenesis of PD. Parkin is expressed in neuronal cell bodies and processes, but not in glial cells in the midbrain, basal ganglia, cerebral cortex, and cerebellum. Patients exhibit a clinical phenotype resembling that seen in sporadic PD. Interestingly, neuropathological findings from patients with Parkin mutations rarely show presence of LBs, although nigrostriatal cell loss may occur. Parkin harbors a great number of exonic variations, including point mutations, insertions, and deletions. Mutations have been identified in populations of all ethnic origins and may constitute one of the most common known genetic causes of early-onset PD (18 49%). The frequency of Parkin mutations decreases with increasing age of disease onset, and mutations are uncommon in patients with late-onset PD. PARK3 The third PARK locus was mapped to chromosome 2p13 by Gasser et al. [8]. Although not yet complete, the mapping indicates association with autosomal dominant PD with late onset and a pathological phenotype including LBs [8]. PARK5 PARK5 is linked to the I93M mutation in the ubiquitin C-terminal hydrolase L1 gene (UCH-L1) in an autosomal dominant German family with typical PD and disease onset around 50 years of age [9]. UCH-L1, also known as PGP9.5, is a neuron-specific enzyme and one of the most abundant proteins in the brain, comprising up to 1 2% of the total soluble brain protein [10]. It is a component of the ubiquitin proteasome system, which degrades damaged proteins [10]. Immunoreactivity of UCH-L1 has been detected in eosinophilic cytoplasmic LBs within remaining dopamine cells in the substantia nigra in neurodegenerative disease, making the gene a suitable candidate for PD [11]. The I93M missense mutation has so far only been identified in two siblings of the affected German family, and has not been found in other PD families. It should be noted that there is a lack of segregation of I93M in the German family. Another variant, S18Y in UCH-L1, has been suggested to be protective, as it has been found to be inversely associated with sporadic PD [12]. In vitro studies show that UCH-L1 exerts two opposing enzymatic activities that affect a-synuclein degradation. As a monomer, UCH-L1 hydrolyzes poly-ubiquitin chains, which promotes ubiquitination and proteasomal degradation of a-synuclein [13]. As a dimer, UCH-L1 ligates ubiquitin to a-synuclein via a K63 linkage that spares it from proteasomal degradation. The I93M mutation inhibits the hydrolyzation and favors dimerization, whereas the S18Y variant encodes a protein that is unable to dimerize, and therefore favors degradation of a-synuclein. FEBS Journal 275 (2008) ª 2008 The Authors Journal compilation ª 2008 FEBS 1379

4 Genetics of Parkinson s disease A. C. Belin and M. Westerlund PARK6 The PARK6 locus and the gene encoding PTENinduced putative kinase 1 (PINK1) was originally mapped in three European PD families by Valente et al. in 2004 [14]. The PARK6 locus is located at chromosome 1p35 p36 and is associated with autosomal recessive early-onset PD (onset age < 50 years) and a typical parkinsonian phenotype; however, mutations have also been found in rare, possibly sporadic, early-onset cases [15]. The mutations found in PINK1 are distributed throughout the gene and have been found in populations of different geographical origins, including Europe, Asia, and North America. PINK1 is a tumor suppressor with a serine threonine kinase and a mitochondrial targeting motif, making it prone to accumulate in the intermembranous space of mitochondria. The function of PINK1 has not yet been fully revealed, but it has been suggested to have a protective effect on neurons against stress induced by mitochondrial dysfunction [16]. PARK7 In 2001, the seventh PARK locus (PARK7) was found to be linked to autosomal recessive early-onset parkinsonism in a Dutch PD family [17]. Two years later, Bonifati et al. reported a deletion and an L166P substitution in the DJ-1 gene in a Dutch and an Italian family that were associated with PARK7 and led to loss of gene function [18]. DJ-1 mutations are recessively inherited and result in PD with early onset; however, the mutations only account for a low number of PD cases. The L166P mutation was later found to destabilize the protein, inducing rapid proteasomal degradation [19]. DJ-1 is an oncogene localized to the cytoplasm and mitochondria of neurons, and is suggested to participate in response to oxidative stress, as it changes its protein properties to a more acidic form following paraquat-induced oxidative stress [20]. PARK8 The PARK8 locus was identified on chromosome 12p11.2 q13.1 in a Japanese autosomal dominant PD family in 2002 [21]. The gene linked to disease in this locus was later identified as that encoding leucine-rich repeat kinase 2 (LRRK2) by Paisan-Ruiz et al. (2004) [22]. Mutations in this gene have been reported to be associated with both familial and apparently sporadic PD, and, to date, constitute the most common cause of PD. The first mutations in LRRK2 were discovered in a Basque PD family, and the protein was therefore given the name Dardarin, derived from the Basque word dardara, meaning tremor [22]. Owing to extensive investigation of LRRK2 during recent years, five putatively pathogenic mutations, R1441C G H, Y1699C, G2019S, I2020T, and G2385R, and several others not known to be pathogenic have been identified. G2019S alone is responsible for up to 6% of hereditary and 1 2% of sporadic cases; however, in certain populations, such as North African Arabs, the mutation frequency is as high as 41% [1]. Overall, mutations in LRRK2 are estimated to account for up to 10% of autosomal dominant familial PD cases. Patients with LRRK2 mutations typically have late disease onset and exhibit a wide range of pathologies that can differ between or within families. The physiological function of LRRK2 is still unclear, but the protein has been suggested to be involved in protein protein interactions, maintenance of neurites, and regulation of neuronal survival. LRRK2 is also of particular interest, as it was discovered to be the first of all the PD genes to relate specifically to the dopamine system [23]. It is expressed in the striatum, the target area of the nigrostriatal dopamine neurons, suggesting that LRRK2 malfunction in the striatum is particularly relevant for PD pathogenesis. PARK9 The ninth PARK locus linked to PD is located on chromosome 1p36 [24], and it harbors the P-type ATPase gene ATP13A2. Mutations in this gene have been identified in consanguineous subjects from an Arab family with Kufor Rakeb syndrome [25]. Affected individuals display an autosomal recessive form of parkinsonism with pyramidal degeneration and cognitive dysfunction, but they also show features not seen in PD. Recently, a study was published reporting ATP13A2 variants associated with more typical early-onset parkinsonism in Brazil and Italy [26]. PARK10 PARK10 was identified on chromosome 1p32 in an Icelandic idiopathic PD population using genome-wide linkage analysis [27]. The study has not yet been confirmed in other PD materials, and the candidate gene remains to be identified. PARK11 The PARK11 locus has been linked to the long arm of chromosome 2 (2q36 q37) [28]. No gene has been identified, and the linking of PD to this locus is still 1380 FEBS Journal 275 (2008) ª 2008 The Authors Journal compilation ª 2008 FEBS

5 A. C. Belin and M. Westerlund Genetics of Parkinson s disease controversial, due to the absence of positive replication in genome-wide association studies. PARK12 PARK12 is the first PD locus linked to the X-chromosome, and was discovered by Pankratz et al. [29]. To date, no genes carrying mutations that are linked to affected family members have been identified. PARK13 The gene encoding HtrA serine peptidase 2 (HTRA2) is the candidate gene at the PARK13 locus on chromosome 2p13 [30]. HTRA2 is a nuclear-encoded protein located to the intermembranous space of the mitochondria and released into the cytosol during apoptosis. Two gene variants, A141S and G399S, have been identified in a German idiopathic PD case-control material leading to defective activation of protease activity and inducing mitochondrial dysfunction in vitro [30]. Conclusion Parkinson s disease is a heterogeneous disorder mainly caused by genetic risk factors that, alone or possibly in combination with the environment, alter susceptibility to the disease. Owing to the great diversity in pathology between PD cases, it seems likely that several molecular pathways and networks involving different genes and downstream effectors affect the survival of dopamine neurons in the substantia nigra. Identification of families carrying mutations in PARK genes has shifted the weight of evidence towards genetic causes of PD (Table 1). It is apparent that the genetic component of PD plays a much more important role in the pathophysiology than previously thought. Reasons why the genetic risk factors have been underestimated in the past could be the relatively high age of disease onset and the reduced penetrance of mutations in some of the PARK genes. The increased longevity seen today facilitates investigation of larger families with several affected generations. However, mapping of genetic loci in families and identification of mutations polymorphisms in case control materials is complex, which is why replication studies and meta-analyses are valuable in order to determine clinical relevance. With the increasing number of genetic markers being identified, the use of methodologically consistent approaches is critical in order to deliver consistent and reproducible results. Several factors, including sample size, diagnostic errors, population-specific gene gene interactions, genes with different modes of inheritance, population heterogeneity, and stratification may influence the outcome of a study and have to be adjusted for if possible. Further adding to the complexity are the presence of phenocopies and differences in mutation frequency between populations. As genetic screening techniques become more rapid and efficient in identification of new candidate genes, there is an increasing need to understand the pathological processes in which the genes are involved and to identify the main interacting players. To unravel gene function, several in vivo and in vitro systems are used, including transgenic animal models, cell culture systems and gene protein expression analyses. These studies have identified mitochondrial and ubiquitin proteasome dysfunction, abnormal protein aggregation and phosphorylation, oxidative stress, apoptosis and inflammation as plausible causes of PD. The findings of these studies could in turn result in identification of new therapeutic targets and improved diagnosis and treatment, and possibly also in individual genetic testing, although this is still controversial. The medical treatment used for PD today is based on dopamine replacement in combination with nondopaminergic treatment as well as surgery. These treatments are effective in reducing the motor complications associated with the disease; however, there is currently no treatment that effectively relieves the depression, dementia, hallucinations or autonomic and sleep disturbances. Even more important is to find therapeutic targets that slow the disease progression or, even better, prevent the disease onset. The possible main targets for therapeutic intervention would be modulation of the function of LRRK2 or interfering with the expression and accumulation of a-synuclein in LBs. Another option would be to manipulate the function of Parkin, PINK1 or DJ-1, as there is increasing evidence that they are all involved in a common pathway. In order to develop better ways of combating PD, or better still, prevent clinical symptoms altogether, one must decipher the causes of disease and, in doing so, take into account that there are different forms of PD and that any given phenotype may possibly result from different genotypes. The identification of genetic risk factors for PD should allow insights into the pathophysiological mechanisms underlying the disease and thereby aid in the development of novel classes of drugs that are able to prevent and or counteract disease. Acknowledgements We would like to acknowledge the Swedish Research Council, Ha llstens Forskningsstiftelse, the Swedish FEBS Journal 275 (2008) ª 2008 The Authors Journal compilation ª 2008 FEBS 1381

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