Hereditary early-onset Parkinson's disease caused by mutations in PINK1

  • Science. 2004 May 21;304(5674):1158-60. doi: 10.1126/science.1096284.
Enza Maria Valente  1 ,  Patrick M Abou-Sleiman ,  Viviana Caputo ,  Miratul M K Muqit ,  Kirsten Harvey ,  Suzana Gispert ,  Zeeshan Ali ,  Domenico Del Turco ,  Anna Rita Bentivoglio ,  Daniel G Healy ,  Alberto Albanese ,  Robert Nussbaum ,  Rafael González-Maldonado ,  Thomas Deller ,  Sergio Salvi ,  Pietro Cortelli ,  William P Gilks ,  David S Latchman ,  Robert J Harvey ,  Bruno Dallapiccola ,  Georg Auburger ,  Nicholas W Wood
Affiliations
  • 1. CSS IRCCS, Mendel Institute, viale Regina Margherita 261, 00198 Rome, Italy. [email protected]
PMID: 15087508 DOI: 10.1126/science.1096284
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.