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Autosomal Recessive, Early-Onset Parkinson's Disease

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Autosomal Recessive, Early-Onset Parkinson's Disease Autosomal recessive, early-onset Parkinson’s disease Vincenzo Bonifati This study was performed at the Department of Clinical Genetics, Erasmus MC Rotterdam, The Netherlands. Vincenzo Bonifati gratefully acknowledges the collaboration with the Department of Epidemiology and Biostatistics, Erasmus MC Rotterdam; the Department of Neurology, Erasmus MC Rotterdam; the INSERM U289, Hôpital de la Salpêtrière, Paris, France; and the Department of Neurological Sciences, University “La Sapienza”, Roma, Italy. The printing of this thesis was supported by the “Internationale Stichting Alzheimer Onderzoek”, and Roche Nederland B.V. Cover: incuse stater, a silver coinage of Sybaris, ca 550-510 b. C., and a masterpiece of the archaic art of the “Great Greece”. ISBN 90-9017491-5 © V. Bonifati, 2003 No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means, without permission of the author. The copyright of the published papers remains with the publishers. Layout: Tom de Vries Lentsch Printed by: Optima Grafi sche Communicatie, Rotterdam Autosomal recessive, early-onset Parkinson’s disease Proefschrift Ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam Op gezag van de Rector Magnifi cus Prof.dr.S.W.J. Lamberts en volgens besluit van het College voor Promoties De openbare verdediging zal plaatsvinden op woensdag 10 december 2003 om 13.45 uur door Vincenzo Bonifati geboren te Castrovillari Promotiecommissie Promotoren: Prof. dr. B.A. Oostra Prof. dr. P. Heutink Overige leden: Prof. dr. C.M. van Duijn Prof. dr. M.H. Breuning Dr. J. C. van Swieten Contents 1 Introduction 1.1 Genetics of the Mendelian forms, and genome-wide linkage screens in 11 classical forms of Parkinson’s disease 1.2 Pathogenesis of Parkinson’s disease – the contribution of D-synuclein and 43 parkin 1.3 Scope of this thesis 63 2 Experimental work 2.1 Association between early-onset Parkinson’s disease and mutations in 69 the parkin gene 2.2 Three parkin gene mutations in a sibship with autosomal recessive early 79 onset parkinsonism 2.3 Pseudo-dominant inheritance and exon 2 triplication in a family with 85 parkin gene mutations 2.4 How much phenotypic variation can be attributed to parkin genotype? 91 2.5 PARK7, a novel locus for autosomal recessive early-onset parkinsonism, 103 on chromosome 1p36 2.6 Localization of autosomal recessive early-onset parkinsonism to 111 chromosome 1p36 (PARK7) in an independent dataset 2.7 Clinical features and neuroimaging of PARK7-linked parkinsonism 117 2.8 Mutations in the DJ-1 gene associated with autosomal recessive 127 early-onset parkinsonism 2.9 Linking DJ-1 to neurodegeneration 139 3 General discussion 147 Summary 161 Samenvatting 163 Riassunto 166 Curriculum Vitae 168 Selected publications 169 Dankwoord 173 Publications based on the studies described in this thesis Chapter 1.1 Bonifati V, Heutink P. Chromosome 1 and other hotspots for Parkinson disease genes. In: Kahle P and Haass C (Editors), Molecular Mechanisms of Parkinson’s Disease. Landes Bioscience Publishers, in press. Chapter 2.1 Lucking CB, Durr A, Bonifati V, Vaughan J, De Michele G, Gasser T, Harhangi BS, Meco G, Denefl e P, Wood NW, Agid Y, Brice A. Association between early-onset Parkinson’s disease and mutations in the parkin gene. New England Journal of Medicine 2000; 342: 1560-1567. Chapter 2.2 Bonifati V, Lucking CB, Fabrizio E, Periquet M, Meco G, Brice A. Three parkin gene mutations in a sibship with autosomal recessive early onset parkinsonism. Journal of Neurology Neurosurgery and Psychiatry 2001; 71: 531-534. Chapter 2.3 Lucking CB, Bonifati V, Periquet M, Vanacore N, Brice A, Meco G. Pseudo-dominant inheritance and exon 2 triplication in a family with parkin gene mutations. Neurology 2001; 57: 924-927. Chapter 2.4 Lohmann E, Periquet M, Bonifati V, Wood NW, De Michele G, Bonnet AM, Fraix V, Broussolle E, Horstink MW, Vidailhet M, Verpillat P, Gasser T, Nicholl D, Teive H, Raskin S, Rascol O, Destee A, Ruberg M, Gasparini F, Meco G, Agid Y, Durr A, Brice A. How much phenotypic variation can be attributed to parkin genotype? Annals of Neurology 2003; 54: 176-185. Chapter 2.5 van Duijn CM, Dekker MC, Bonifati V, Galjaard RJ, Houwing-Duistermaat JJ, Snijders PJ, Testers L, Breedveld GJ, Horstink M, Sandkuijl LA, van Swieten JC, Oostra BA, Heutink P. PARK7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. American Journal of Human Genetics 2001; 69: 629-634. Chapter 2.6 Bonifati V, Breedveld GJ, Squitieri F, Vanacore N, Brustenghi P, Harhangi BS, Montagna P, Cannella M, Fabbrini G, Rizzu P, van Duijn CM, Oostra BA, Meco G, Heutink P. Localization of autosomal recessive early-onset parkinsonism to chromosome 1p36 (PARK7) in an independent dataset. Annals of Neurology 2002; 51: 253-256. Chapter 2.7 Dekker M, Bonifati V, van Swieten J, Leenders N, Galjaard RJ, Snijders P, Horstink M, Heutink P, Oostra B, van Duijn C. Clinical features and neuroimaging of PARK7-linked parkinsonism. Movement Disorders 2003; 18: 751-757. Chapter 2.8 Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P. Mutations in the DJ-1 gene associated with autosomal recessive early- onset parkinsonism. Science 2003; 299: 256-259. Chapter 2.9 Bonifati V, Oostra BA, Heutink P. Linking DJ-1 to neurodegeneration offers novel insights for understanding the pathogenesis of Parkinson’s disease. Journal of Molecular Medicine, in press. Introduction1 Chapter 1.1 Genetics of the Mendelian forms, and genome-wide linkage screens in classical forms of Parkinson’s disease INTRODUCTION Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease, with a prevalence of 1-2% in the population aged t 65 years.1 The disease is clinically defi ned by the presence of parkinsonism (the combination of akinesia, resting tremor, and muscular rigidity), and a good response to dopaminergic therapy. These features are associated at pathological level with neuronal loss and gliosis, mainly in the substantia nigra pars compacta but also in other brain areas, and formation of cytoplasmic inclusions called Lewy bodies (LB) and Lewy neurites in the surviving neurons.2 The role of genetics versus environment in the etiology of PD has been a matter of debate for more than a century, with alternating fortunes. Genetics versus Environment Strong support for the “environmental” theories came from the occurrence of post- encephalitic parkinsonism after the pandemia of infl uenza in the early 1900s, and after the more recent discovery of permanent parkinsonism in humans caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a substance similar to widely used pesticides.3 However, the disease has survived the era of the post-encephalitic cohort, and despite the epidemiological association of PD with environmental factors such as rural living and occupational exposure to pesticides, a putative MPTP-like toxin causing PD has not been identifi ed yet. Familial aggregation of PD has been noted for long,4, 5 re-emerging consistently in the subsequent surveys6, 7 until the current time,8, 9 and supporting a role for genetic factors. Studies in PD twins, however, have produced confl icting results. According to the largest of such studies,10 the pattern of concordance in monozygotic versus dizygotic twins differs critically on the basis of PD onset age, in keeping with a prominent role for genetic factors in early onset cases (before 50 years of age, according to that study), but a negligible role in late-onset PD, which represent the vast majority of cases. However, the sample size was still relatively small (less than 200 twins with PD), and the study was based on a cross-sectional, clinical survey.10 The period elapsing before a co-twin develops clinically overt PD, becoming concordant, can be as long as 20 years,11 indicating that a longer follow-up is important in studying PD twins. Moreover, when positron emission tomography was used to assess the integrity of the nigrostriatal dopaminergic system, the concordance between monozygotic twins appeared signifi cantly higher than that of dizygotic twins, once again supporting the role of genetic factors.12 PD appears today as a sporadic disorder in most patients. However, in a signifi cant percentage of cases (10-15% in most studies), the disease runs in families without a clearcut Mendelian pattern of inheritance. Recent segregation analyses found evidence for a major gene with reduced, age-related penetrance.8, 13 However, these studies might be biased toward segregation patterns consistent with major genes depending on the ascertainment strategy, and the observed scenario also supports the contention of common PD being a complex trait determined by several genetic 11 Chapter 1.1 as well as non-genetic factors. More rarely, the PD phenotype is transmitted as a Mendelian trait, with either autosomal dominant or recessive inheritance. In the last few years, family-based linkage analysis and positional cloning has led to the identifi cation of loci and genes for rare monogenic forms (table 1),14, 15 and more recently, of loci harbouring susceptibility genes for common, non-Mendelian PD forms of late-onset (table 1).16, 17 Although the monogenic forms so far identifi ed explain a very small fraction of PD cases at the population level, they are proving to be extremely useful in promoting
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