Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP.
PTEN-induced putative kinase 1 (Pink1) is a recently identified gene linked to a recessive form of familial Parkinson's disease (PD). The kinase contains a mitochondrial localization sequence and is reported to reside, at least in part, in mitochondria. However, neither the manner by which the loss of Pink1 contributes to dopamine neuron loss nor its impact on mitochondrial function and relevance to death is clear. Here, we report that depletion of Pink1 by RNAi increased neuronal toxicity induced by MPP(+). Moreover, wild-type Pink1, but not the G309D mutant linked to familial PD or an engineered kinase-dead mutant K219M, protects neurons against MPTP both in vitro and in vivo. Intriguingly, a mutant that contains a deletion of the putative mitochondrial-targeting motif was targeted to the cytoplasm but still provided protection against 1-methyl-4-phenylpyridine (MPP(+))/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity. In addition, we also show that endogenous Pink1 is localized to cytosolic as well as mitochondrial fractions. Thus, our findings indicate that Pink1 plays a functional role in the survival of neurons and that cytoplasmic targets, in addition to its other actions in the mitochondria, may be important for this protective effect.
Haque
M Emdadul
ME
Ottawa Health Research Institute, Neuroscience Group, University of Ottawa, Ottawa, ON, Canada.
Thomas
Kelly J
KJ
D'Souza
Cheryl
C
Callaghan
Steve
S
Kitada
Tohru
T
Slack
Ruth S
RS
Fraser
Paul
P
Cookson
Mark R
MR
Tandon
Anurag
A
Park
David S
DS
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival / Q000235:genetics; D003593:Cytoplasm / Q000201:enzymology; D015259:Dopamine Agents / Q000633:toxicity; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000201:enzymology; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics; D011494:Protein Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D000099202:PTEN-Induced Putative Kinase
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015259:Dopamine Agents; D009498:Neurotoxins; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase