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Title: The neurodegenerative disease Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) : cellular defects due to loss of sacsin function
Author: Duncan, Emma Jane
ISNI:       0000 0004 7652 0221
Awarding Body: Queen Mary University of London
Current Institution: Queen Mary, University of London
Date of Award: 2016
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Sacsin, which is mutated in the neurodegenerative disease Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS), is a 520 kDa modular protein with regions of homology to molecular chaperones and domains linking to the ubiquitin proteasome system. This suggests a role in proteostasis. Previously, sacsin has been shown to partially localise with mitochondria, and loss of sacsin results in elongated and dysfunctional mitochondria. Moreover, alterations in neurofilaments have recently been reported in a mouse model of ARSACS. Despite these findings, pathophysiological mechanisms of ARSACS are poorly understood. The aim of this thesis was to elucidate the cellular role of sacsin by determining how loss of its function leads to the observed mitochondrial and intermediate filament defects. This hoped to shed light on the mechanism of disease in ARSACS. The results indicate that the mitochondrial elongation seen in ARSACS is likely due to reduced mitochondrial localisation of the essential fission factor DRP1. This may be mediated by loss of function of a complex involving sacsin and dynactin-6, a subunit of the dynein-dynactin motor complex, which has previously been shown to be required for DRP1 mitochondrial recruitment. DRP1-mediated mitochondrial fission is necessary for mitochondrial quality control; hence a disruption to mitochondrial quality control is likely to occur in sacsin deficient cells, which may explain the mitochondrial dysfunction in ARSACS. Furthermore, sacsin null cells display a dramatic collapse and perinuclear bundling of the vimentin intermediate filament network. This is coupled with the displacement of cellular organelles, particularly mitochondria, early endosomes and the Golgi, which accumulate at the periphery of the vimentin bundle. These are characteristic features of aggresome formation, indicating an aggregation of misfolded protein, which occurs due to disrupted proteostasis. Further supporting this, the proteostasis components ubiquitin, HSP70, LAMP2 and p62 are recruited to the perinuclear vimentin bundles. In summary, the findings of this thesis indicate a role for sacsin in mitochondrial and protein quality control, the dysfunction of which is likely to be particularly detrimental in neurons. Mitochondrial dysfunction along with protein misfolding and aggregation are implicated in many neurodegenerative diseases, and ARSACS is no exception.
Supervisor: Not available Sponsor: Ataxia Charlevoix-Saguenay Foundation ; Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Endocrinology ; Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay ; ARSACS ; Neurodegenerative Disease ; Sacsin