Hereditary early-onset Parkinson's disease caused by mutations in PINK1.
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.
Valente
Enza Maria
EM
CSS IRCCS, Mendel Institute, viale Regina Margherita 261, 00198 Rome, Italy. e.valente@css-mendel.it
Abou-Sleiman
Patrick M
PM
Caputo
Viviana
V
Muqit
Miratul M K
MM
Harvey
Kirsten
K
Gispert
Suzana
S
Ali
Zeeshan
Z
Del Turco
Domenico
D
Bentivoglio
Anna Rita
AR
Healy
Daniel G
DG
Albanese
Alberto
A
Nussbaum
Robert
R
González-Maldonado
Rafael
R
Deller
Thomas
T
Salvi
Sergio
S
Cortelli
Pietro
P
Gilks
William P
WP
Latchman
David S
DS
Harvey
Robert J
RJ
Dallapiccola
Bruno
B
Auburger
Georg
G
Wood
Nicholas W
NW
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D045744:Cell Line, Tumor; D018389:Codon, Nonsense; D005091:Exons; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008564:Membrane Potentials; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D014162:Transfection; D000099202:PTEN-Induced Putative Kinase
D018389:Codon, Nonsense; D007976:Leupeptins; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde