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dc.contributor.authorBradshaw, Teisha Y.
dc.identifier.citationBradshaw, T.Y. 2014. The Cellular Phenotype of the Neurodegenerative Disease Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay. Queen Mary University of London.en_US
dc.description.abstractAutosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is an early onset neurodegenerative disorder resulting from mutations in the SACS gene that encodes the protein sacsin. Sacsin is a 520kDa multi-domain protein localised at the cytosolic face of the outer mitochondrial membrane with suggested roles in proteostasis and most recently in the regulation of mitochondrial morphology. An excessively interconnected mitochondrial network was observed as a consequence of reduced levels of sacsin protein following SACS knockdown in neuroblastoma cells as well as in an ARSACS patient carrying the common Quebec homozygous SACS mutation 8844delT. Moreover, it was suggested that sacsin has a role in mitochondrial fission as it was found to interact with mitochondrial fission protein Dynamin related protein 1 (Drp1). The aim of this thesis was to explore sacsin’s role in the regulation of mitochondrial morphology and dynamics in non-Quebec ARSACS patients and sacsin knockdown fibroblasts. This study shows that loss of sacsin function promotes a more interconnected mitochondrial network in non-Quebec ARSACS patients and in sacsin knockdown fibroblasts. Moreover, recruitment of the essential mitochondrial fission protein Drp1 to the mitochondria was significantly reduced in ARSACS patient cells and in sacsin knockdown fibroblasts. This reduced recruitment of Drp1 to mitochondria also occurred when cells were treated to induce mitochondrial fission. Furthermore, both the size and intensity of Drp1 foci localised to the mitochondria were significantly reduced in both sacsin knockdown and patient fibroblasts. Finally, reduced ATP production, decreased respiratory capacity of mitochondria and an increase in mitochondrial reactive oxygen species demonstrated impaired mitochondrial function in ARSACS patient and sacsin knockdown fibroblasts. These results suggest a role for sacsin in the stabilisation or recruitment of cytoplasmic Drp1 to prospective sites of mitochondrial fission similar to that observed by other mitochondrial fission accessory proteins.en_US
dc.description.sponsorshipAtaxia Charlevoix-Saguenay Foundation; Queen Mary, University of Londonen_US
dc.publisherQueen Mary University of Londonen_US
dc.subjectAutosomal recessive spastic ataxia of Charlevoix Saguenayen_US
dc.subjectNeurodegenerative diseasesen_US
dc.subjectSACS geneen_US
dc.titleThe Cellular Phenotype of the Neurodegenerative Disease Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay.en_US
dc.rights.holderThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author

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    Theses Awarded by Queen Mary University of London

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