Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1

EM Valente, PM Abou-Sleiman, V Caputo, MMK Muqit… - Science, 2004 - science.org
EM Valente, PM Abou-Sleiman, V Caputo, MMK Muqit, K Harvey, S Gispert, Z Ali
Science, 2004science.org
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 …
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.
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