Genetics of Parkinson's disease

Purpose of ReviewParkinson's disease is the second most common neurodegenerative disorder and affects 2% of the population over the age of 60 years. Due to the increasing proportion of elderly individuals in developed countries, Parkinson's disease and related neurodegenerative disorders represent a growing burden on the health care system. In the majority of cases, the cause of the disease is still unknown, and its elucidation remains one of the major challenges of the neurosciences. Recent findings in rare genetic forms of Parkinson's disease have allowed the development of novel animal models, providing a basis for a better understanding of the molecular pathogenesis of the disease, setting the stage for the development of novel treatment strategies. Recent findingsSeveral novel genes for monogenic forms of Parkinson's disease, such as PINK-1 for an autosomal-recessive early-onset variant, and LRRK2 for a relatively common late-onset autosomal-dominant form have recently been discovered, and several novel animal models have been generated on the basis of genes that had been found earlier. SummaryThe combination of genetic, pathologic and molecular findings provide increasing evidence that the pathways identified through the cloning of different disease genes are interacting on different levels and share several major pathogenic mechanisms.

[1]  A. Bentivoglio,et al.  PINK1 mutations are associated with sporadic early‐onset parkinsonism , 2004, Annals of neurology.

[2]  P. V. van Haastert,et al.  Roc, a Ras/GTPase domain in complex proteins. , 2003, Biochimica et biophysica acta.

[3]  Joachim Klose,et al.  Mitochondrial Dysfunction and Oxidative Damage in parkin-deficient Mice* , 2004, Journal of Biological Chemistry.

[4]  B. Müller-Myhsok,et al.  A susceptibility locus for Parkinson's disease maps to chromosome 2p13 , 1998, Nature Genetics.

[5]  Nicholas W Wood,et al.  A common LRRK2 mutation in idiopathic Parkinson's disease , 2005, The Lancet.

[6]  Matthew J. Farrer,et al.  α-synuclein gene haplotypes are associated with Parkinson’s disease , 2001 .

[7]  N. Quinn,et al.  The role of pathogenic DJ‐1 mutations in Parkinson's disease , 2003, Annals of neurology.

[8]  K. Marder,et al.  Risk of Parkinson's disease among first-degree relatives , 1996, Neurology.

[9]  J. Aharon-Peretz,et al.  Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. , 2004, The New England journal of medicine.

[10]  R. Nussbaum,et al.  Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1 , 2004, Science.

[11]  M. Farrer,et al.  Clinical Findings in a Large Family With a Parkin Ex3Δ40 Mutation , 2004 .

[12]  N. Quinn,et al.  DJ-1 mutations in Parkinson's disease. , 2004, Journal of neurology, neurosurgery, and psychiatry.

[13]  T. Foroud,et al.  Genes influencing Parkinson disease onset , 2004, Neurology.

[14]  Shinsei Minoshima,et al.  Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase , 2000, Nature Genetics.

[15]  Janel O. Johnson,et al.  Parkin disease in a Brazilian kindred: Manifesting heterozygotes and clinical follow‐up over 10 years , 2005, Movement disorders : official journal of the Movement Disorder Society.

[16]  D. Goldstein,et al.  UCHL1 is a Parkinson's disease susceptibility gene. , 2004 .

[17]  M. Chesselet,et al.  Alpha-synuclein and transgenic mouse models , 2004, Neurobiology of Disease.

[18]  Nobutaka Hattori,et al.  Novel PINK1 mutations in early‐onset parkinsonism , 2004, Annals of neurology.

[19]  J. Hoenicka,et al.  The new mutation, E46K, of α‐synuclein causes parkinson and Lewy body dementia , 2004, Annals of neurology.

[20]  Andrew Lees,et al.  Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease , 2004, Neuron.

[21]  M. Farrer,et al.  Interaction of α‐synuclein and tau genotypes in Parkinson's disease , 2005 .

[22]  D. Hernandez,et al.  Lewy bodies and parkinsonism in families with parkin mutations , 2001, Annals of neurology.

[23]  Patrizia Rizzu,et al.  Mutations in the DJ-1 Gene Associated with Autosomal Recessive Early-Onset Parkinsonism , 2002, Science.

[24]  Pietro Cortelli,et al.  Homozygous PINK1 C‐terminus mutation causing early‐onset parkinsonism , 2004, Annals of neurology.

[25]  R. Nussbaum,et al.  Regulation of alpha-synuclein expression by poly (ADP ribose) polymerase-1 (PARP-1) binding to the NACP-Rep1 polymorphic site upstream of the SNCA gene. , 2005, American journal of human genetics.

[26]  J. Noth,et al.  DJ-1 (PARK7) mutations are less frequent than Parkin (PARK2) mutations in early-onset Parkinson disease , 2004, Neurology.

[27]  Mark A. Wilson,et al.  The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Peter T. Lansbury,et al.  Impaired Degradation of Mutant α-Synuclein by Chaperone-Mediated Autophagy , 2004, Science.

[29]  M. Farrer,et al.  α‐Synuclein promoter confers susceptibility to Parkinson's disease , 2004 .

[30]  N. Pedersen,et al.  No evidence for heritability of Parkinson disease in Swedish twins , 2004, Neurology.

[31]  Alexandra Durr,et al.  How much phenotypic variation can be attributed to parkin genotype? , 2003, Annals of neurology.

[32]  Vincenzo Bonifati,et al.  A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease , 2005, The Lancet.

[33]  T. Foroud,et al.  Evaluation of the role of Nurr1 in a large sample of familial Parkinson's disease , 2004, Movement disorders : official journal of the Movement Disorder Society.

[34]  X. Breakefield,et al.  Phenotypic variability in a large kindred (Family LA) with deletions in the parkin gene , 2002, Movement disorders : official journal of the Movement Disorder Society.

[35]  A Dürr,et al.  Causal relation between α-synuclein locus duplication as a cause of familial Parkinson's disease , 2004, The Lancet.

[36]  M. Iwata,et al.  Parkin-positive autosomal recessive juvenile parkinsonism with α-synuclein-positive inclusions , 2004, Neurology.

[37]  T. Kondo,et al.  Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q , 1998, Neurology.

[38]  Georg Auburger,et al.  The ubiquitin pathway in Parkinson's disease , 1998, Nature.

[39]  J. C. Greene,et al.  Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Eden R Martin,et al.  Fibroblast growth factor 20 polymorphisms and haplotypes strongly influence risk of Parkinson disease. , 2004, American journal of human genetics.

[41]  J. Trojanowski,et al.  Initiation and Synergistic Fibrillization of Tau and Alpha-Synuclein , 2003, Science.

[42]  Timothy Lynch,et al.  Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. , 2005, American journal of human genetics.

[43]  M. Pericak-Vance,et al.  Linkage disequilibrium and haplotype tagging polymorphisms in the Tau H1 haplotype , 2004, Neurogenetics.

[44]  Dopaminergic dysfunction in unrelated, asymptomatic carriers of a single parkin mutation , 2005, Neurology.

[45]  Thomas Gasser,et al.  Point mutations in exon 1 of the NR4A2 gene are not a major cause of familial Parkinson′s disease , 2003, Neurogenetics.

[46]  Janel O. Johnson,et al.  Analysis of the PINK1 gene in a large cohort of cases with Parkinson disease. , 2004, Archives of neurology.

[47]  C. Ross,et al.  Parkin Mediates Nonclassical, Proteasomal-Independent Ubiquitination of Synphilin-1: Implications for Lewy Body Formation , 2005, The Journal of Neuroscience.

[48]  M. Farrer,et al.  Parkin variants in North American Parkinson's disease: Cases and controls , 2003, Movement disorders : official journal of the Movement Disorder Society.

[49]  M. Cookson,et al.  Mitochondria and Dopamine New Insights into Recessive Parkinsonism , 2004, Neuron.

[50]  David W. Miller,et al.  α-Synuclein in blood and brain from familial Parkinson disease with SNCA locus triplication , 2004, Neurology.

[51]  Tatiana Foroud,et al.  Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease , 2005, The Lancet.

[52]  Z. Wszolek,et al.  Clustering of Parkinson disease: shared cause or coincidence? , 2004, Archives of neurology.

[53]  N. Quinn,et al.  Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations , 2001, Neurology.

[54]  T. Iwatsubo,et al.  Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson's disease. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[55]  J. C. Greene,et al.  Immune responses , 2004 .

[56]  K. Marder,et al.  Distribution, type, and origin of Parkin mutations: Review and case studies , 2004, Movement disorders : official journal of the Movement Disorder Society.

[57]  Thomas Meitinger,et al.  Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology , 2004, Neuron.

[58]  Rina Bandopadhyay,et al.  The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson's disease. , 2004, Brain : a journal of neurology.

[59]  T. Meitinger,et al.  Multiple regions of α‐synuclein are associated with Parkinson's disease , 2005, Annals of neurology.

[60]  Janel O. Johnson,et al.  α-Synuclein Locus Triplication Causes Parkinson's Disease , 2003, Science.

[61]  R. Krüger,et al.  Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7) , 2004, Human mutation.

[62]  G. Schellenberg,et al.  parkin mutation dosage and the phenomenon of anticipation: a molecular genetic study of familial parkinsonism , 2005, BMC neurology.

[63]  D. Schaid,et al.  Familial aggregation of Parkinson's disease: The Mayo Clinic family study , 2004, Annals of neurology.

[64]  Miguel Ángel Martínez,et al.  Genome-wide scan linkage analysis for Parkinson’s disease: the European genetic study of Parkinson’s disease , 2004, Journal of Medical Genetics.

[65]  A J Lees,et al.  Tau gene and Parkinson’s disease: a case–control study and meta-analysis , 2004, Journal of Neurology, Neurosurgery & Psychiatry.

[66]  V. Kostic,et al.  Failure to Find α-Synuclein Gene Dosage Changes in 190 Patients With Familial Parkinson Disease , 2005 .