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PGC-1α in neurodegeneration and ageing

Li, L; (2017) PGC-1α in neurodegeneration and ageing. Doctoral thesis , UCL (University College London). Green open access

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Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common age-related neurodegenerative disorders, affecting millions of people worldwide. There are currently no effective or curative therapies for the treatment of these diseases. Genetic studies have demonstrated that mitochondrial dysfunction and oxidative stress play key roles in the pathogenesis of both AD and PD. Therefore ,genetic or pharmacological interventions targeting these effectors may prove to be useful therapeutic strategies. In my thesis, I focus on the transcriptional cofactor PGC-1α,a key modulator in many biological processes, including mitochondrial biogenesis, the oxidative stress defence system, thecircadian clock, and protein quality control. The possible relevance of this gene in the pathogenesis of AD andPDcame to light with the demonstration that PGC-1αgene expression levels are decreased in the post - mortem brain tissues of bothAD and PD patients. Consistent with this,I have shown that up-regulation of PGC-1α in the neurons of a Drosophila model of Aβ toxicity rescue s lifespan, the behavioural phenotypes and circadian rhythm disruption. I demonstrated that amelioration of Aβ toxicity is associated with improved mitochondrial homeostasis and activation of theER unfolded protein response (UPRER). In keeping with this, I also found that rifampicin, an antibiotic used in the treatment of tuberculosis and leprosy, also activated the UPRER and rescued the neurotoxicity in Aβ-expressing flies. These findings suggest thatstimulating the UPRER, either by increasing intraneuronal PGC -1α levels or through oral administration of rifampicin, may offer significant therapeutic benefits in AD. Contrary to the results seen using Aβ-expressing flies, I demonstrated that over - expression of PGC-1α did not rescue the neurotoxic phenotypes in Drosophila models of familial PD, lacking PINK1 or parkin. Given an increasing ageing population coupled with the high prevalence of age related diseases there is an urgent need for the development of pharmacological agents that can improve healthy aging. PGC-1α has been identified as a novel modulator of fly ageing. The precise mechanisms involved however have not been fully elucidated. Here I also identified the transcription factor GA-binding protein (dGABPα), downstream of PGC-1α, as a key modulator of fly ageing. dGABPα gain-of-function extends female lifespan via mechanisms beyond dietary restriction (DR), with an associated reduction in IIS/mTOR signalling. In addition, over-expression of dGABPα improved gut homeostasis by delaying age-related over-proliferation of intestinal stem cells. Additionally, dGABPα gain-of-function flies showed resistance to xenobiotic stress. Finally, I demonstrated that dGABPα up-regulated ImpL2, the insulin ligand binding protein, which down-regulates IIS and extends lifespan. Given the evolutionary conserved effects of reduced IIS/mTOR signalling, these findings suggest that GABP αmay be an important modulator of mammalian ageing and a potential therapeutic target in the treatment of age-related diseases.

Type: Thesis (Doctoral)
Title: PGC-1α in neurodegeneration and ageing
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Third party copyright material has been removed from ethesis.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
URI: https://discovery.ucl.ac.uk/id/eprint/1544181
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