Parkin protects against the toxicity associated with mutant α-Synuclein

Proteasome dysfunction selectively affects catecholaminergic neurons

Leonard Petrucelli, Casey O'Farrell, Paul J. Lockhart, Melisa Baptista, Kathryn Kehoe, Liselot Vink, Peter Choi, Benjamin Wolozin, Matthew Farrer, John Hardy, Mark R. Cookson

Research output: Contribution to journalArticle

465 Citations (Scopus)

Abstract

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 α-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 α-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 α-synuclein or proteasome inhibition in these cells. Therefore, parkin and α-synuclein are linked by common effects on a pathway associated with selective cell death in catecholaminergic neurons.

Original languageEnglish (US)
Pages (from-to)1007-1019
Number of pages13
JournalNeuron
Volume36
Issue number6
DOIs
StatePublished - Dec 19 2002

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Synucleins
Proteasome Inhibitors
Proteasome Endopeptidase Complex
Neurons
Ubiquitin-Protein Ligases
Poisons
Mesencephalon
Parkinson Disease
Cell Death
Proteins

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Parkin protects against the toxicity associated with mutant α-Synuclein : Proteasome dysfunction selectively affects catecholaminergic neurons. / Petrucelli, Leonard; O'Farrell, Casey; Lockhart, Paul J.; Baptista, Melisa; Kehoe, Kathryn; Vink, Liselot; Choi, Peter; Wolozin, Benjamin; Farrer, Matthew; Hardy, John; Cookson, Mark R.

In: Neuron, Vol. 36, No. 6, 19.12.2002, p. 1007-1019.

Research output: Contribution to journalArticle

Petrucelli, L, O'Farrell, C, Lockhart, PJ, Baptista, M, Kehoe, K, Vink, L, Choi, P, Wolozin, B, Farrer, M, Hardy, J & Cookson, MR 2002, 'Parkin protects against the toxicity associated with mutant α-Synuclein: Proteasome dysfunction selectively affects catecholaminergic neurons', Neuron, vol. 36, no. 6, pp. 1007-1019. https://doi.org/10.1016/S0896-6273(02)01125-X
Petrucelli, Leonard ; O'Farrell, Casey ; Lockhart, Paul J. ; Baptista, Melisa ; Kehoe, Kathryn ; Vink, Liselot ; Choi, Peter ; Wolozin, Benjamin ; Farrer, Matthew ; Hardy, John ; Cookson, Mark R. / Parkin protects against the toxicity associated with mutant α-Synuclein : Proteasome dysfunction selectively affects catecholaminergic neurons. In: Neuron. 2002 ; Vol. 36, No. 6. pp. 1007-1019.
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