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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Apoptosis
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COS Cells
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Cell Line, Tumor
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Codon, Nonsense
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Exons
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Humans
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Leupeptins / pharmacology
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Membrane Potentials
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Mitochondria / enzymology
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Mitochondria / metabolism*
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Molecular Sequence Data
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Mutation*
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Mutation, Missense
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Neurons / metabolism
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Neurons / physiology
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Oxidative Stress
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Parkinson Disease / enzymology
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Parkinson Disease / genetics*
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Parkinson Disease / metabolism
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Protein Kinases / chemistry
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Protein Kinases / genetics*
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Protein Kinases / metabolism*
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Protein Structure, Tertiary
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Transfection
Substances
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Codon, Nonsense
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Leupeptins
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Protein Kinases
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PTEN-induced putative kinase
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde
Associated data
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GENBANK/AB053323
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GENBANK/AF316873
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GENBANK/AK075225
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GENBANK/AL391357
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GENBANK/BC009534
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GENBANK/BC028215