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Unravelling the mechanisms by which mutations in TG6 cause ataxia

Turberville, Shannon 2019. Unravelling the mechanisms by which mutations in TG6 cause ataxia. PhD Thesis, Cardiff University.
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Abstract

Transglutaminase 6 (TG6) is an enzyme involved in the transamidation, deamidation and isopeptide cleavage of target substrates. TG6 is predominantly expressed in the brain and has been linked to progressive neurological dysfunction, most commonly ataxia. Spinocerebellar ataxia (SCA) is a group of neurological diseases characterised by progressive imbalance and cognitive impairment. Mutations in TG6 have been specifically linked to SCA35 using exome sequencing and genetic linkage analysis. Recent work investigating the TG6 mutants in a cellular context has identified that some mutants initiate the unfolded protein response and are targeted for proteolytic degradation by the proteasome, whilst other are not (Tripathy et al. 2017). In order to enable future intervention in the disease process, it is important to establish the underlying mechanism by which the pathogenic TG6 mutants cause neurodegeneration. Here, the structure and function of wild-type TG6 and the pathogenic TG6 mutants were first analysed using a novel bioinformatic method to predict the impact of TG6 mutations. The biochemical methods optimised using TG2 and TG2 GTP binding mutants showed high sensitivity whereby the point mutations which affect TG regulation, activation and structure could be characterised. These methods in turn were used to distinguish the various molecular mechanisms the TG6 mutants undertake to cause neuronal cell death, work which has not been previously been carried out. Cellular studies provided further evidence for the diverse pathogenic mechanisms involved in the pathogenesis of SCA35 and highlighted the involvement of the unfolded protein response in those TG6 mutants impacting TG6 structure. Ongoing research will provide valuable insight into the mechanisms of neuronal cell death and will aid in the validation of the bioinformatic method. Consequently, a treatment for SCA35 can be developed.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Dentistry
Subjects: Q Science > Q Science (General)
Uncontrolled Keywords: transglutaminase; spinocerebellar ataxia; TG6
Date of First Compliant Deposit: 16 March 2020
Last Modified: 16 Mar 2023 02:30
URI: https://orca.cardiff.ac.uk/id/eprint/130399

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