title: Hereditary early-onset Parkinson's disease caused by mutations in PINK1.
abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6). Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6. We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid. Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress. These data provide a direct molecular link between mitochondria and the pathogenesis of PD.
authors.affiliation: CSS IRCCS, Mendel Institute, viale Regina Margherita 261, 00198 Rome, Italy. e.valente@css-mendel.it
authors.forename: Enza Maria
authors.initials: EM
authors.lastname: Valente
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Abou-Sleiman
authors.forename: Viviana
authors.initials: V
authors.lastname: Caputo
authors.forename: Miratul M K
authors.initials: MM
authors.lastname: Muqit
authors.forename: Kirsten
authors.initials: K
authors.lastname: Harvey
authors.forename: Suzana
authors.initials: S
authors.lastname: Gispert
authors.forename: Zeeshan
authors.initials: Z
authors.lastname: Ali
authors.forename: Domenico
authors.initials: D
authors.lastname: Del Turco
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Bentivoglio
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Healy
authors.forename: Alberto
authors.initials: A
authors.lastname: Albanese
authors.forename: Robert
authors.initials: R
authors.lastname: Nussbaum
authors.forename: Rafael
authors.initials: R
authors.lastname: González-Maldonado
authors.forename: Thomas
authors.initials: T
authors.lastname: Deller
authors.forename: Sergio
authors.initials: S
authors.lastname: Salvi
authors.forename: Pietro
authors.initials: P
authors.lastname: Cortelli
authors.forename: William P
authors.initials: WP
authors.lastname: Gilks
authors.forename: David S
authors.initials: DS
authors.lastname: Latchman
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Harvey
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Georg
authors.initials: G
authors.lastname: Auburger
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D045744:Cell Line, Tumor; D018389:Codon, Nonsense; D005091:Exons; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008564:Membrane Potentials; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D014162:Transfection; D000099202:PTEN-Induced Putative Kinase
chemical_list: D018389:Codon, Nonsense; D007976:Leupeptins; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde