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Published Online: 24 November 2014

The Ubiquitin-Proteasome System in Neurodegeneration

Publication: Antioxidants & Redox Signaling
Volume 21, Issue Number 17

Abstract

Significance: Impairment of the ubiquitin-proteasome system (UPS) has been implicated in the pathogenesis of a wide variety of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases. The most significant risk factor for the development of these disorders is aging, which is associated with a progressive decline in UPS activity and the accumulation of oxidatively modified proteins. To date, no therapies have been developed that can specifically up-regulate this system. Recent Advances: In the neurodegenerative brain, dysfunction of the UPS has been associated with the deposition of ubiquitinated protein aggregates and widespread disruption of the proteostasis network. Recent research has identified further evidence of impairment in substrate ubiquitination and proteasomal degradation, which could contribute to the loss of cellular proteostasis in neurodegenerative disease. Novel strategies for activation of the UPS by genetic manipulation and treatment with synthetic compounds have also recently been identified. Critical Issues: Here, we discuss the specific roles of the UPS in the healthy central nervous system and establish how dysfunctional components can contribute to neurotoxicity in the context of disease. Future Directions: Knowledge of the UPS components that are specifically or preferentially involved in neurodegenerative disease will be critical in the development of targeted therapies which aim at limiting the accumulation of misfolded proteins without gross disturbance of this major proteolytic pathway. Antioxid. Redox Signal. 21, 2302–2321.

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cover image Antioxidants & Redox Signaling
Antioxidants & Redox Signaling
Volume 21Issue Number 17December 10, 2014
Pages: 2302 - 2321
PubMed: 24437518

History

Published in print: December 10, 2014
Published online: 24 November 2014
Published ahead of print: 27 February 2014
Published ahead of production: 18 January 2014
Accepted: 18 January 2014
Received: 6 January 2014

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Chris McKinnon
Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom.
Sarah J. Tabrizi
Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom.

Notes

Address correspondence to:Prof. Sarah J. TabriziDepartment of Neurodegenerative DiseaseUCL Institute of NeurologyQueen SquareLondon WC1N 3BGUnited Kingdom
E-mail: [email protected]

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