Investigating the role of RNA Binding Proteins and Modulators of Mitochondrial Function in Neurodegenerative Disease

Abstract

Neurodegenerative diseases have a devastating impact on patients, and they are becoming more prevalent due to the increasing age of the global population. However, despite intensive research there are no disease-modifying therapies for any neurodegenerative conditions. Dysregulation of RNA binding protein (RBP) and mitochondrial function are key hallmarks of the molecular pathology of neurodegenerative diseases such as amyotrophic lateral sclerosis, polyglutamine (polyQ) disorders and Parkinson’s disease. This thesis aims to contribute to the understanding of how RBPs mediate neurodegenerative pathology, and to investigate pharmacological modulation of mitochondrial function as a neuroprotective strategy. The expression of the RBP scaffold attachment factor 1 (SAFB1) was investigated in degenerating human brains. These studies revealed a novel, abnormal SAFB1 cytoplasmic expression pattern associated specifically with polyQ disease including spinocerebellar ataxias and Huntington’s disease. Spinocerebellar ataxia type 1 is caused by an expansion of the polyQ tract in the ATXN1 gene. The interaction between SAFB1 protein and pathological expanded tandem repeat RNA (xtrRNA) was therefore investigated. RNA immunoprecipitation confirmed SAFB1 interacted with ATXN1 transcripts and demonstrated that a pathological CAG expansion confers a relative increase in the level of ATXN1 associated with SAFB1. This result suggests that an interaction between SAFB1 and expanded polyQ tracts may result in the mislocalisation of SAFB1 to the cytoplasm in degenerating polyQ neurons. Furthermore, these findings support the hypothesis that it is RBP dysfunction that leads to neurodegenerative pathology. Drugs that promote mitochondrial function may be effective in treating neurodegenerative conditions such as Parkinson’s disease. Using an in-vitro phenotypic screen, kenpaullone, a GSK-3 beta/CDK5 inhibitor, was identified as a novel modulator of parkin recruitment. Kenpaullone was also found to increase mitochondrial length, protect against mitochondrial toxins and alter respiratory function. Based on these findings, further investigations are recommended to explore the potential neuroprotective actions of kenpaullone like drugs.

Date of Award	23 Jun 2020
Original language	English
Awarding Institution	The University of Bristol
Supervisor	James B Uney (Supervisor) & Liang-Fong Wong (Supervisor)