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Pale Body-Like Inclusion Formation and Neurodegeneration following Depletion of 26S Proteasomes in Mouse Brain Neurones are Independent of alpha-Synuclein

Paine, SML; Anderson, G; Bedford, K; Lawler, K; Mayer, RJ; Lowe, J; Bedford, L; (2013) Pale Body-Like Inclusion Formation and Neurodegeneration following Depletion of 26S Proteasomes in Mouse Brain Neurones are Independent of alpha-Synuclein. PLOS ONE , 8 (1) , Article ARTN e54711. 10.1371/journal.pone.0054711. Green open access

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Abstract

Parkinson’s disease (PD) is characterized by the progressive degeneration of substantia nigra pars compacta (SNpc) dopaminergic neurones and the formation of Lewy bodies (LB) in a proportion of the remaining neurones. α-synuclein is the main component of LB, but the pathological mechanisms that lead to neurodegeneration associated with LB formation remain unclear. Three pivotal elements have emerged in the development of PD: α-synuclein, mitochondria and protein degradation systems. We previously reported a unique model, created by conditional genetic depletion of 26S proteasomes in the SNpc of mice, which mechanistically links these three elements with the neuropathology of PD: progressive neurodegeneration and intraneuronal inclusion formation. Using this model, we tested the hypothesis that α-synuclein was essential for the formation of inclusions and neurodegeneration caused by 26S proteasomal depletion. We found that both of these processes were independent of α-synuclein. This provides an important insight into the relationship between the proteasome, α-synuclein, inclusion formation and neurodegeneration. We also show that the autophagy-lysosomal pathway is not activated in 26S proteasome-depleted neurones. This leads us to suggest that the paranuclear accumulation of mitochondria in inclusions in our model may reflect a role for the ubiquitin proteasome system in mitochondrial homeostasis and that neurodegeneration may be mediated through mitochondrial factors linked to inclusion biogenesis.

Type: Article
Title: Pale Body-Like Inclusion Formation and Neurodegeneration following Depletion of 26S Proteasomes in Mouse Brain Neurones are Independent of alpha-Synuclein
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0054711
Publisher version: http://dx.doi.org/10.1371/journal.pone.0054711
Language: English
Additional information: © 2013 Paine et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
UCL classification: UCL
URI: https://discovery.ucl.ac.uk/id/eprint/1388819
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