Petrucelli L, O'Farrell C, Lockhart PJ, Baptista M, Kehoe K, Vink L, Choi P, Wolozin B, Farrer M, Hardy J, Cookson MR. Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron. 2002 Dec 19;36(6):1007-19. PubMed.

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  1. Since Parkinson's disease can develop as a result of mutations in several different genes, finding a common link among these gene products can provide a unifying explanation of the pathways that ultimately lead to neuronal death. The interesting study by Petrucelli et al is an example of such progress. It links the cellular rescuing effects of Parkin with the toxicity of mutant α-synuclein. The authors also confirm the 2001 observation by Tanaka, Ross and colleagues that mutant α-synuclein impairs proteasomal activity. Similarly, the finding that the toxicity of mutant α-synuclein is selective for dopaminergic neurons is consistent with an earlier report by Xu, Yankner and colleagues (see news story). Petrucelli's paper adds further support to the role of proteasomal degradation of proteins and their accumulation in the pathogenesis of Parkinson's disease.

    References:

    Tanaka Y, Engelender S, Igarashi S, Rao RK, Wanner T, Tanzi RE, Sawa A, L Dawson V, Dawson TM, Ross CA. Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Hum Mol Genet. 2001 Apr 15;10(9):919-26. PubMed.

    View all comments by Maral Mouradian

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  1. Parkinson's Proteins and the Proteasome—The Plot Thickens