Investigating the neuroprotective function of TLDc proteins

A recent World Health Organisation Global Burden of Disease study reports a yearly increase in the prevalence of neurodegenerative diseases, with more than 100 million people worldwide expected to be living with dementia by 2050. These disorders represent a range of neurological conditions characterised by selective neuronal cell death; no effective treatments have been developed, with the available therapy only able to reduce the symptoms in some cases. Although etiology of neurodegenerative diseases is not well understood, some common pathological features are shared between them, including protein aggregation and oxidative stress. Identification of the molecular mechanisms underlying these processes would therefore deepen our understanding of the disease pathogenesis and help in the search for new therapeutic targets. Members of a conserved protein family (TLDc) have been shown in recent years to protect neurons from oxidative insults in vitro and in vivo and play a role in oxidative stress response regulation via unknown mechanism. In addition, TLDc mutations are causative in range of neurological disorders, some characterised by neurodegeneration. Therefore, further analysis of this particular protein family may provide new insights into fundamental protective mechanisms that could be harnessed in the future. The aim of this thesis was to investigate the mechanism of action of the TLDc protein oxidation resistance 1 (Oxr1) in oxidative stress protection and in the maintenance of neural tissue homeostasis. Using a combination of in vitro assays and in animal models with disruption or overexpression of Oxr1, I have shown that Oxr1 interacts with the potent antioxidant enzyme peroxiredoxin-2 where it regulates its post-translational modifications and oligomerisation in a brain-region specific manner. I have also for the first time discovered a molecular function of Oxr1 by showing it possesses holdase chaperone activity in vitro, suggesting it acts as a putative chaperone. Next, to understand the cause of neurodegeneration in the Oxr1 knockout mouse, transcriptional profiling was carried out, revealing an induction of presymptomatic neuroinflammatory markers, suggesting Oxr1 is critical for the normal inflammatory response in the brain. I have also produced preliminary data suggesting a role for Oxr1 in autophagy. Finally, computational analysis of transcriptional activity and regulation of TLDc family members suggests high degree of functional conservation between TLDc genes and their involvement in processes throughout the body, proposing novel directions for future studies. Together, my results contribute to our understanding of the functions of TLDc genes in the CNS and the role of Oxr1 in oxidative stress protection and proteostasis.