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

Science. 2004 May 21;304(5674):1158-60. doi: 10.1126/science.1096284. Epub 2004 Apr 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • COS Cells
  • Cell Line, Tumor
  • Codon, Nonsense
  • Exons
  • Humans
  • Leupeptins / pharmacology
  • Membrane Potentials
  • Mitochondria / enzymology
  • Mitochondria / metabolism*
  • Molecular Sequence Data
  • Mutation*
  • Mutation, Missense
  • Neurons / metabolism
  • Neurons / physiology
  • Oxidative Stress
  • Parkinson Disease / enzymology
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism
  • Protein Kinases / chemistry
  • Protein Kinases / genetics*
  • Protein Kinases / metabolism*
  • Protein Structure, Tertiary
  • Transfection


  • Codon, Nonsense
  • Leupeptins
  • Protein Kinases
  • PTEN-induced putative kinase
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde

Associated data

  • GENBANK/AB053323
  • GENBANK/AF316873
  • GENBANK/AK075225
  • GENBANK/AL391357
  • GENBANK/BC009534
  • GENBANK/BC028215