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Failure of the ubiquitin–proteasome system in Parkinson's disease

Abstract

Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by degeneration of dopamine-containing neurons in the midbrain. In cases of familial PD, mutations that lead to failure of the ubiquitin–proteasome system (UPS) have been identified. These genetic abnormalities do not occur in sporadic PD, but we propose that impairment of the UPS could also contribute to neurodegeneration in this disorder. We discuss evidence that failure of the UPS is a common aetiopathogenic factor that underlies the development of familial and sporadic PD, an idea that might help to explain clinical and pathological differences and similarities in these disorders.

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Figure 1: Degradation of abnormal proteins by the ubiquitin–proteasome system and impairments that lead to the development of Parkinson's disease.

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Acknowledgements

K.S.P.M. and O.I. are supported by grants from the National Institutes of Health, the Century Foundation and the Parkinson Alliance. C.W.O. is supported by a grant from the National Institutes of Health and by grants from the Lowenstein Foundation and the Bachmann-Strauss Foundation. P.J. is supported by grants from the Parkinson's Disease Society and the National Parkinson Foundation.

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DATABASE LINKS

Parkinson's disease

α-synuclein

parkin

ubiquitin

UCHL1

26S proteasomes

neurofilaments

torsin-A

AR–JP

dementia with Lewy bodies

Pael receptor

CDCrel-1

spinocerebellar ataxia

Jun kinase

PA700

PA28

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McNaught, K., Olanow, C., Halliwell, B. et al. Failure of the ubiquitin–proteasome system in Parkinson's disease. Nat Rev Neurosci 2, 589–594 (2001). https://doi.org/10.1038/35086067

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