Investigating the DNA damage response in neurodegeneration

George, Charlotte Marie (2023). Investigating the DNA damage response in neurodegeneration. University of Birmingham. Ph.D.

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Abstract

Elevated levels of DNA damage are found in neurodegenerative diseases, including Parkinson’s disease, Amyotrophic lateral sclerosis, and Alzheimer’s Disease. It is not known whether the DNA damage is a cause or a consequence of the pathology. DNA damage in the nervous system has the potential to cause aberrant cell cycle re-entry, trigger apoptosis or induce Alzheimer’s disease-like pathological changes, including
Tau phosphorylation and amyloid beta (Aβ) plaque deposition. Previous work has shown that knocking down key players involved in the response to DNA double strand breaks, including ataxia-telangiectasia-mutated kinase (ATM) and checkpoint kinase 2 (Chk2), elicits a neuroprotective in a Drosophila model of Alzheimer’s disease. Here, I investigated potential mechanisms downstream of the ATM-Chk2 signalling pathway to identify those that may contribute to the neurotoxicity in our Drosophila Alzheimer’s disease model. I demonstrate the involvement of p53, a key downstream target of ATM and Chk2 in the DNA damage response and show that blocking caspase activity protects against amyloid induced toxicity. Surprisingly, I was not able to find evidence of aberrant cell cycle re-entry or apoptosis in the brains of Drosophila expressing toxic Aβ, which indicates a potential non-apoptotic role for caspases in amyloid induced neurotoxicity

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):