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Quality Control Gone Wrong: Mitochondria, Lysosomal Storage Disorders and Neurodegeneration.

Osellame, LD; Duchen, MR; (2014) Quality Control Gone Wrong: Mitochondria, Lysosomal Storage Disorders and Neurodegeneration. Br J Pharmacol , 171 (8) pp. 1958-1972. 10.1111/bph.12453. Green open access

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Abstract

The eukaryotic cell possesses specialized pathways to turnover and degrade redundant proteins and organelles. Each pathway is unique and responsible for degradation of distinctive cytosolic material. The ubiquitin-proteasome system and autophagy (chaperone-mediated, macro, micro and organelle specific), act synergistically to maintain proteostasis. Defects in this equilibrium can be deleterious at cellular and organism level, giving rise to various disease states. Dysfunction of quality control pathways are implicated in in neurodegenerative diseases, and appear particularly important in Parkinson's disease and the Lysosomal storage disorders. Neurodegeneration resulting from impaired degradation of ubiquitinated proteins and α-synuclein is often accompanied by mitochondrial dysfunction. Mitochondria have evolved to control a diverse number of processes including cellular energy production, calcium signaling and apoptosis and like every other organelle within the cell, they must be 'recycled.' Failure to do so is potentially lethal as these once indispensible organelles become destructive, leaking reactive oxygen species and activating the intrinsic cell death pathway. This process is paramount in neurons which have an absolute dependence on mitochondrial oxidative phosphorylation as they cannot up-regulate glycolysis. As such mitochondrial bioenergetic failure can underpin neural death and neurodegenerative disease. In this review we discuss the links between cellular quality control and neurodegenerative diseases associated with mitochondrial dysfunction, with particular attention to the emerging links between Parkinson's and Gaucher diseases in which defective quality control is a defining factor.

Type: Article
Title: Quality Control Gone Wrong: Mitochondria, Lysosomal Storage Disorders and Neurodegeneration.
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/bph.12453
Publisher version: http://dx.doi.org/10.1111/bph.12453
Additional information: © 2013 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Autophagy, Gaucher Disease, Lysosomal Storage Disorders, Lysosome, Mitochondria, Neurodegeneration, Parkinson's Disease, Ubiquitin-Proteasome System
UCL classification: UCL > Provost and Vice Provost Offices
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 Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: http://discovery.ucl.ac.uk/id/eprint/1411115
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