Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.577436
Title: Investigation of changes in mitochondrial dynamics in motor neuron diseases
Author: Duffy, L.
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2013
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Abstract:
Changes in mitochondrial dynamics, including alterations in the fusion/fission balance, have repeatedly been observed in ageing and neurodegenerative disease, including ALS. We investigated the effect of ageing or disease on mitochondrial network complexity in primary dermal fibroblasts, derived from ALS patients or controls. Increased network complexity during ageing was observed in the control cohort, though motility was unaffected. Conversely, network complexity decreased in the sporadic ALS patient cohort upon ageing. We speculate that this alteration in mitochondrial dynamics may contribute to the significant detrimental effect age has on disease prognosis in ALS. In mutant TARDBP (mTARDBP) patient fibroblasts, a trend towards increased network complexity compared to age-matched controls was observed. Moreover, despite no discernible differences in ATP levels in the mTARDBP fibroblasts compared to control samples, microarray analysis hinted at changes in two metabolic pathways, glycolysis and the TCA cycle, both known to influence mitochondrial dynamics. Subtle changes in the interaction of the ER and mitochondria were also observed in the mTDP-43 fibroblasts. Furthermore, expression of two autophagy genes, MAP1S and Atg12, was significantly altered in the mTARDBP fibroblasts. However, LC3-II western blotting in either mTDP-43 or mC9ORF72 fibroblasts did not reveal any significant differences, suggesting that changes in autophagy is not the primary cellular process responsible for the mitochondrial morphology alterations. HSP is characterised by defects in axonal transport, including mitochondrial transport. A mouse model of SPG4-mediated HSP showed axonal swellings in cortical neurons, correlating with impaired axonal transport. We showed that Tro19622 (a microtubule-interacting drug) did not ameliorate the number of axonal swellings in the mutant neurons, though alterations in microtubule integrity were apparent. Conversely, HDAC6 inhibitor, Tubastatin A, reduced the number of axonal swellings in SPG4-mutant neurons to wild type levels, suggesting that microtubule acetylation state could be an interesting therapeutic target for future investigation in HSP.
Supervisor: Grierson, A. J. ; Shaw, P. J. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.577436  DOI: Not available
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