Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons.
One hypothesis for the etiology of Parkinson's disease (PD) is that subsets of neurons are vulnerable to a failure in proteasome-mediated protein turnover. Here we show that overexpression of mutant alpha-synuclein increases sensitivity to proteasome inhibitors by decreasing proteasome function. Overexpression of parkin decreases sensitivity to proteasome inhibitors in a manner dependent on parkin's ubiquitin-protein E3 ligase activity, and antisense knockdown of parkin increases sensitivity to proteasome inhibitors. Mutant alpha-synuclein also causes selective toxicity to catecholaminergic neurons in primary midbrain cultures, an effect that can be mimicked by the application of proteasome inhibitors. Parkin is capable of rescuing the toxic effects of mutant alpha-synuclein or proteasome inhibition in these cells. Therefore, parkin and alpha-synuclein are linked by common effects on a pathway associated with selective cell death in catecholaminergic neurons.
Petrucelli
Leonard
L
Neurogenetics Laboratory, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA.
O'Farrell
Casey
C
Lockhart
Paul J
PJ
Baptista
Melisa
M
Kehoe
Kathryn
K
Vink
Liselot
L
Choi
Peter
P
Wolozin
Benjamin
B
Farrer
Matthew
M
Hardy
John
J
Cookson
Mark R
MR
D000818:Animals; D000831:Animals, Newborn; D002395:Catecholamines / Q000378:metabolism*; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008025:Ligases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D013378:Substantia Nigra / Q000378:metabolism* / Q000503:physiopathology; D051843:Synucleins; D014407:Tumor Cells, Cultured; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation / Q000235:genetics; D051844:alpha-Synuclein
D002395:Catecholamines; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D008025:Ligases