Genetic Analysis of Pathways to Parkinson Disease

In this review I outline the arguments as to whether we should consider Parkinson disease one or more than one entity and discuss genetic findings from Mendelian and whole-genome association analysis in that context. I discuss what the demonstration of disease spread implies for our analysis of the genetic and epidemiologic risk factors for disease and outline the surprising fact that we now have genetically identified on the order of half our risk for developing the disease. In this review I outline the arguments as to whether we should consider Parkinson disease one or more than one entity and discuss genetic findings from Mendelian and whole-genome association analysis in that context. I discuss what the demonstration of disease spread implies for our analysis of the genetic and epidemiologic risk factors for disease and outline the surprising fact that we now have genetically identified on the order of half our risk for developing the disease. We have two goals in the genetic analysis of disease: the first is to increase the accuracy of risk prediction, with an intention of getting better at diagnosing the disease earlier and perhaps targeting presymptomatic therapy; the second is to define the pathways that lead to cell death so that we can design approaches that intervene in those pathways and act as mechanistic therapies. In Parkinson disease, a neurodegenerative disorder affecting movement and usually characterized by the presence of α-synuclein containing Lewy bodies in damaged neurons, genetic analysis has been remarkably successful, with many mendelian loci already described, a common high-risk variant identified and many common low-risk variants recently elucidated. This is particularly remarkable because epidemiologic investigations preceding the identification of the α-synuclein (SNCA) locus consistently suggested that genes were unimportant in disease etiology. As our knowledge of the disease has increased over the last 15 years, the proportion of risk assigned to the environment has consistently decreased and, while associations with environmental factors have been confirmed (such as that showing a negative association with smoking), no environmental risk factor with a convincing pathogenic role in the disease has yet been described. We and others have recently comprehensively reviewed the identification of mendelian genes for Parkinson disease (Hardy et al., 2009Hardy J. Lewis P. Revesz T. Lees A. Paisan-Ruiz C. The genetics of Parkinson's syndromes: A critical review.Curr. Opin. Genet. Dev. 2009; 19: 254-265Crossref PubMed Scopus (173) Google Scholar, Klein and Lohmann-Hedrich, 2007Klein C. Lohmann-Hedrich K. Impact of recent genetic findings in Parkinson's disease.Curr. Opin. Neurol. 2007; 20: 453-464Crossref PubMed Scopus (92) Google Scholar, Cookson and Bandmann, 2010Cookson M.R. Bandmann O. Parkinson's disease: Insights from pathways.Hum. Mol. Genet. 2010; 19: R21-R27Crossref PubMed Scopus (134) Google Scholar). Given this, my purpose in this review is to discuss four issues:1.To discuss whether all the identified genes relate to single entity and what pathways have been identified as relevant to disease.2.To discuss how the identification of risk loci through genome-wide association studies relate to the Mendelian genes and whether we should inevitably expect those low-risk loci to encode proteins that map onto the same pathways as those identified through the identification of Mendelian loci:3.To discuss the implication of permissive templating (“prionoid”) behavior of α-synuclein to the concept of disease risk4.To discuss the proportion of risk for disease that has been identified so far. Table 1 lists the loci at which pathogenic mutations lead to parkinsonism (for references, see Hardy et al., 2009Hardy J. Lewis P. Revesz T. Lees A. Paisan-Ruiz C. The genetics of Parkinson's syndromes: A critical review.Curr. Opin. Genet. Dev. 2009; 19: 254-265Crossref PubMed Scopus (173) Google Scholar). These include those loci traditionally noted as “Parkinson loci” as well as others that are not, including MAPT, SCA2, SCA3, and spastacsin, which can clinically present as Parkinson disease but often is clinically distinct. In some diseases, most clearly Alzheimer disease, the disease is defined by its pathology. In Parkinson disease, the disease has been traditionally defined clinically, but the vast majority of cases of disease have the pathology of Lewy bodies (Hughes et al., 1993Hughes A.J. Daniel S.E. Blankson S. Lees A.J. A clinicopathologic study of 100 cases of Parkinson's disease.Arch. Neurol. 1993; 50: 140-148Crossref PubMed Scopus (843) Google Scholar). However, while the vast majority of idiopathic cases have Lewy bodies, the genetic forms of the disease have variable pathologies (Table 1). Thus part of my intention in this review is to question how we should group the genetic loci if we are trying to understand the pathogenesis of the disorder. Should we use clinical criteria (in which case, all of the loci may stake a claim as to involvement), or should we use pathological criteria, in which case the number clearly involved is much smaller although for many, the pathology has not been documented?Table 1Mendelian Genes that Lead to Parkinsonism and Their PathologyLocusGenesClinical FeaturesPathologyDominantPARK1/4α-SynucleinTypical PD but can sometimes have a dementia presentationLewy bodiesPARK8LRRK2Typical PDUsually Lewy bodies: sometime tangles, sometimes neitherFTDP-17MAPTMost mutations have a dementia phenotype but some have a typical PD presentationTau/tangle pathologySCA3Ataxin3Usually ataxia in Europeans, but often Parkinsonian especially in AfricansProbably not Lewy bodies. Probably polyglutamine inclusionsSCA2Ataxin2Usually ataxia in Europeans, but often Parkinsonian especially in AsiansProbably not Lewy bodies. Probably polyglutamine inclusionsRecessivePARK2ParkinVery slowly progressive early onset disease usually with sleep benefitUsually not Lewy bodiesPARK6PINK1Usually very slowly progressive early onset disease usually with sleep benefitOne case with Lewy bodiesPARK7DJ-1Little data, but seems similar to parkinNot knownPARK9ATP13A2Aggressive and complex parkinsonism with many additional featuresNot knownPARK14PLA2G6Aggressive and complex parkinsonism with many additional featuresLewy bodiesSPG11SpatacsinUsually spastic paraplegia but sometimes aggressive and complex parkinsonism with additional featuresNot knownHigh-Risk LocusGaucher's (1) locusGBATypical PDLewy bodiesLow-Risk LociSNCATypical PDLewy bodiesMAPTLewy bodies (though tau pathology not systematically assessedLRRK2Typical PDLewy bodiesHLATypical PDLewy bodies Open table in a new tab The major argument in favor of using pathological criteria for the definition of disease is an analogy: in Alzheimer disease, the loci identified for the disorder, APP, and the presenilins clearly map into one pathway (Hardy and Selkoe, 2002Hardy J. Selkoe D.J. The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics.Science. 2002; 297: 353-356Crossref PubMed Scopus (11121) Google Scholar): defining the disease clinically would lead to confusion with a large series of other genes (MAPT, PRNP, PGRN, etc.) being grouped with them. A second argument is that both clinically and pathologically the disease seems to spread along neuronal pathway. This notion of the disease spreading has been most vividly captured by the work of Braak and colleagues (Braak et al., 2003Braak H. Del Tredici K. Rüb U. de Vos R.A. Jansen Steur E.N. Braak E. Staging of brain pathology related to sporadic Parkinson's disease.Neurobiol. Aging. 2003; 24: 197-211Abstract Full Text Full Text PDF PubMed Scopus (7336) Google Scholar) and is supported by the idea that misfolded synuclein acts as a template for other synuclein to deposit upon (see below). It is difficult to see how this templating pathogenesis could be relevant to those forms of the disease without Lewy body pathology. There are several arguments against using pathological criteria. First, the pathology of (for example) LRRK2 mutation carriers is variable with the majority of cases having Lewy bodies, but a minority have tangles and some having other pathology (Zimprich et al., 2004Zimprich A. Biskup S. Leitner P. Lichtner P. Farrer M. Lincoln S. Kachergus J. Hulihan M. Uitti R.J. Calne D.B. et al.Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.Neuron. 2004; 44: 601-607Abstract Full Text Full Text PDF PubMed Scopus (2318) Google Scholar). Second, a few compound heterozygote parkin mutation cases (e.g., Farrer et al., 2010Farrer M. Chan P. Chen R. Tan L. Lincoln S. Hernandez D. Forno L. Gwinn-Hardy K. Petrucelli L. Hussey J. et al.Lewy bodies and parkinsonism in families with parkin mutations.Ann. Neurol. 2010; 50: 293-300Crossref Scopus (433) Google Scholar) and some clearly simple heterozygous parkin and some, at least, PINK1 cases have been reported to have typical Lewy body disease suggesting that the pathogeneses of the two forms of the disease are not dissimilar (Samaranch et al., 2010Samaranch L. Lorenzo-Betancor O. Arbelo J.M. Ferrer I. Lorenzo E. Irigoyen J. Pastor M.A. Marrero C. Isla C. Herrera-Henriquez J. Pastor P. PINK1-linked parkinsonism is associated with Lewy body pathology.Brain. 2010; 133: 1128-1142Crossref PubMed Scopus (197) Google Scholar). Third, although mutations in MAPT (microtubule-associated protein tau, or often referred to simply as tau) lead to a disorder that can closely clinically resemble idiopathic Parkinson disease, the majority have a dementing syndrome that is clearly different from Parkinson disease; however, the MAPT/tau haplotype shows an association with disease (see below) strongly suggesting that the pathogenic cascades in the tauopathies must be related to those in the synucleinopathies. A practical argument against using pathological criteria is that for many syndromes, we do not know the underlying pathology of many of the syndromes, and a lesson to be drawn from the case of LRRK2 mutations is that pathology can be variable. As Table 1 illustrates, there are many syndromes that can masquerade as Parkinson disease, some of which (e.g., SCA2 and SCA3) almost certainly have different pathogenic mechanisms since they are both polyglutamine repeat disorders. Furthermore, there are clear phenotypic differences between the diseases defined by their genetic etiology. As an example, the Japanese clinicians who first identified PARK2 encoded disease were clear that this was distinct from typical Parkinson disease, with a very prolonged and benign disease duration, profound dopamine sensitivity, and sleep benefit (Yamamura, 2010Yamamura Y. The long journey to the discovery of PARK2.Neuropathology. 2010; (in press. Published online July 27, PubMed Scopus Google PINK1 and et al., E. M. C. A. R. D.J. et Parkinson parkinsonism associated with PINK1 and PubMed Scopus Google Scholar) and encoded diseases similar et al., C. R. M. H. E. P. M. et parkinsonism with to and 2010; PubMed Scopus Google Scholar). This is clearly clinically different from typical idiopathic Parkinson disease (see et al., 1993Hughes A.J. Daniel S.E. Blankson S. Lees A.J. A clinicopathologic study of 100 cases of Parkinson's disease.Arch. Neurol. 1993; 50: 140-148Crossref PubMed Scopus (843) Google Scholar) The pathway that has most clearly of the analysis of the Mendelian genes is a pathway. It is clear that an and a are genetically in the same pathway parkin of and that this pathway is involved in the of damaged et al., J. S. Y. S. S. E. J. M. J.M. J. in PINK1 is by PubMed Scopus Google Scholar, et al., C. M. is for and genetically with PubMed Scopus Google Scholar). and are to be involved in has been to to the and a on the of et al., M.A. R. C. S. D. Cookson M.R. The Parkinson's disease protein is to 2004; PubMed Scopus Google see 2010Cookson M.R. and their on 2010; PubMed Scopus Google Scholar). the of genes are involved in the same or different pathways is not yet the that all genes map onto pathways and all have similar clinical is et al., C. R. M. H. E. P. M. et parkinsonism with to and 2010; PubMed Scopus Google Scholar, et al., S. T. R. L. A. 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A second pathway that is to be involved in Parkinson disease clearly the and are (though the of the is not yet there are between and there are between whether there is or should to be between loci and the loci is not The two loci that all would are to Parkinson disease, and in many the most α-synuclein clearly has a role in et al., K. D. Chen A. R. et with to prolonged in 2002; PubMed Google Scholar) and is related to the complex proteins et al., J. M. T. M. synuclein in and in 2010; (in press. Published online PubMed Scopus Google and, as a LRRK2 is almost certainly involved in cascades and The and pathology of the Parkinson's disease protein 2010; PubMed Scopus Google to et al., D. J. R. T. K. A. The Parkinsonism LRRK2 Full Text Full Text PDF PubMed Scopus Google Scholar, et al., A. K. M. M. M. C. M. A for repeat is involved in 2010; (in press. Published online 27, PubMed Scopus Google Scholar). there is some that LRRK2 and may have a role in the same pathway et al., L. L. H. L. C. J. et repeat the of by 2009; Full Text Full Text PDF PubMed Scopus Google they do not to and their have no to or association studies have our to loci at which genetic to disease for all diseases, are we have in what this common is and how into the of In most of the loci by this are present in more than of the of and, if have the risk increase risk of disease than two over the As a a single in of the risk of Alzheimer disease The majority of low-risk loci for all diseases to their by than through protein In there is an that as the at a locus the more that the have a protein at its et al., Hardy J. H. a of the genetic of Genet. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). In Parkinson disease the fact that the locus was the first to genome-wide is perhaps not surprising et al., J. C. J.M. M. D. Paisan-Ruiz C. Lichtner P. Hernandez et association study genetic risk underlying Parkinson's Genet. 2009; PubMed Scopus Google Scholar) been suggested on the of et al., R. D. T. 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Full Text Full Text PDF PubMed Scopus Google the role has not been one a pathogenic at some of low-risk loci may not be for disease in disease or disease or in the pathways that cell but are involved in the of the this to be the case, is to that in the different diseases, different of the to more or and and their colleagues in studies of with Parkinson disease who clinically and more than Lewy bodies in those This remarkable demonstration that Lewy bodies in the brain of with Parkinson disease et al., E. D. P. Lees A.J. T. S. A. et al.Lewy bodies in in with Parkinson's disease disease PubMed Scopus Google Scholar, et al., Y. R.A. Lewy pathology in in Parkinson's PubMed Scopus Google Scholar) can be in two that the environment the are in is to Lewy body in some that Lewy body from the has the pathology in the et al., P. O. Revesz T. in The of Parkinson's disease pathology PubMed Scopus Google Scholar). 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A. et analysis of mutations in Parkinson's J. 2009; PubMed Scopus Google Scholar). and to a PINK1 mutations are common in disease and may of the disease with an at onset but this is of the order of of the disease et al., P. S. E. S. M. Y. A. A. Parkinson's analysis of the PINK1 in parkinsonism in and PubMed Scopus Google Scholar). Mendelian and identified high-risk loci between and of risk in most so the proportion of risk encoded by common low-risk loci is but seems that in the MAPT, and loci of the order of of risk et al., J. C. J.M. M. D. Paisan-Ruiz C. Lichtner P. Hernandez et association study genetic risk underlying Parkinson's Genet. 2009; PubMed Scopus Google Scholar, et al., A. A. J. D. J. E. et genetic in the is associated with sporadic Parkinson's Genet. 2010; PubMed Scopus Google Scholar). These of from series of cases and are not an that to an of the of risk that has been However, risk into the most common variant identified at and, analysis other risk variants at all of of they that genetic analysis has already identified of the order of half of the risk of getting Parkinson disease. As more loci are and as more analysis is at identified this proportion of identified risk clearly increase The 15 since the identification of the locus in the have in Parkinson to the we now have identified half of the risk of developing the disease. now are our other genes involved in the disease of a more clearly see the We to work whether all the genes I have into one or whether there are two or more α-synuclein and LRRK2 is and protein clearly are to the disease how are they the spread of pathology relate to cell or is simply These are some of the we to genes has the to and should for the disease The last 15 have but there is much work to be we can this into clinical