Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1
Enza Maria Valente, 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- Multidisciplinary
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.