Effects of mitochondrial dysfunction on neurofilament turnover and distribution in human neuroblastoma cells

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Hanes, A, 2010. Effects of mitochondrial dysfunction on neurofilament turnover and distribution in human neuroblastoma cells. PhD, Nottingham Trent University.

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Abstract

A common feature of neurodegenerative conditions including Parkinson’s disease (PD) is the presence of intracytoplasmic proteinacious inclusions. In PD these inclusions are called Lewy bodies (LBs) and contain a number of proteins including α-synuclein, ubiquitin and neurofilaments (NFs). NFs, the intermediate filaments expressed in neuronal cells are responsible for the maintenance of axonal structure. Although NFs were the first proteins identified in LBs their role in PD pathogenesis has not been fully explored. The work presented here attempts to address some of the gaps in the current knowledge concerningNF turnover and the role of NFs in PD using the human SH-SY5Y neuroblastoma cell line, commonly used as a cellular model of neurodegeneration. Mitochondrial dysfunction, dopamine (DA) mediated oxidative stress and impaired protein degradation have all been implicated in PD pathogenesis. The complex I inhibitor MPTP and its active metabolite (MPP+) induce Parkinsonism in humans and other primates and have been extensively used as PD mimetics in both cellular and animal models. Addition of specific protease inhibitors in the presence of cycloheximide (an inhibitor of new protein synthesis) revealed that NF-heavy chains are degraded by macroautophagy and cathepsin D, possibly with some involvement of cysteine cathepsin, but not calpain or the ubiquitin proteasome system (UPS). This is in contrast to α-synuclein which was degraded by macroautophagy, the UPS and calpain. Treatment with MPP+ did not increase NF halflife despite a reduction in the activity of the 20S proteasome, cathepsin D and macroautophagy.

Item Type:	Thesis
Creators:	Hanes, A.
Date:	2010
Rights:	This work is the intellectual property of the author. You may copy up to 5% of this work for private study, or personal, non-commercial research. Any re-use of the information contained within this document should be fully referenced, quoting the author, title, university, degree level and pagination. Queries or requests for any other use, or if a more substantial copy is required, should be directed in the first instance to the author.
Divisions:	Schools > School of Science and Technology
Record created by:	EPrints Services
Date Added:	09 Oct 2015 09:34
Last Modified:	09 Oct 2015 09:34
URI:	https://irep.ntu.ac.uk/id/eprint/130