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The ubiquitin-proteasome system in neurodegeneration

McKinnon, C; Tabrizi, SJ; (2014) The ubiquitin-proteasome system in neurodegeneration. Antioxidants and Redox Signal , 21 (17) pp. 2302-2321. 10.1089/ars.2013.5802. Green open access

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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.

Type: Article
Title: The ubiquitin-proteasome system in neurodegeneration
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1089/ars.2013.5802
Publisher version: http://dx.doi.org/10.1089/ars.2013.5802
Additional information: Final publication is available from Mary Ann Liebert, Inc., publishers http://dx.doi.org/10.1089/ars.2013.5802
Keywords: Animals, Central Nervous System, Humans, Neurodegenerative Diseases, Proteasome Endopeptidase Complex, Ubiquitin
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/1422723
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