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Science 31 October 2003:
Vol. 302. no. 5646, pp. 819 - 822
DOI: 10.1126/science.1087753
Prev | Table of Contents | Next

Review

Molecular Pathways of Neurodegeneration in Parkinson's Disease

Ted M. Dawson1,2,3* and Valina L. Dawson1,2,3,4

Parkinson's disease (PD) is a complex disorder with many different causes, yet they may intersect in common pathways, raising the possibility that neuroprotective agents may have broad applicability in the treatment of PD. Current evidence suggests that mitochondrial complex I inhibition may be the central cause of sporadic PD and that derangements in complex I cause {alpha}-synuclein aggregation, which contributes to the demise of dopamine neurons. Accumulation and aggregation of {alpha}-synuclein may further contribute to the death of dopamine neurons through impairments in protein handling and detoxification. Dysfunction of parkin (a ubiquitin E3 ligase) and DJ-1 could contribute to these deficits. Strategies aimed at restoring complex I activity, reducing oxidative stress and {alpha}-synuclein aggregation, and enhancing protein degradation may hold particular promise as powerful neuroprotective agents in the treatment of PD.

1 Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
2 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
3 Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
4 Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

* To whom correspondence should be addressed. E-mail: tdawson{at}jhmi.edu

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J. Neurosci. 25, 5544-5552
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Expression Profiling of Substantia Nigra in Parkinson Disease, Progressive Supranuclear Palsy, and Frontotemporal Dementia With Parkinsonism.
M. A. Hauser, Y.-J. Li, H. Xu, M. A. Noureddine, Y. S. Shao, S. R. Gullans, C. R. Scherzer, R. V. Jensen, A. C. McLaurin, J. R. Gibson, et al. (2005)
Arch Neurol 62, 917-921
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Increased glutathione S-transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease.
A. J. Whitworth, D. A. Theodore, J. C. Greene, H. Benes, P. D. Wes, and L. J. Pallanck (2005)
PNAS 102, 8024-8029
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