Melandri, Daniela; (2022) Investigating novel pathways regulating mitophagy in Parkinson’s Disease. Doctoral thesis (Ph.D), UCL (University College London).

Preview

Text DMelandri_final thesis for UCL upload.pdf - Accepted Version Download (31MB) | Preview

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease and no disease modifying therapy has been approved as of yet. The analysis of the familial forms of PD has led to the identification of the monogenic causes and has implicated key pathways in the pathogenesis of the diseases. Genome-wide association studies have greatly advanced our understanding of genetic risk of PD. However, identifying the causal genes and their functional significance is challenging. Mitophagy, the selective degradation of damaged mitochondria, is a key causative pathway in monogenic PD, but whether it is relevant for sporadic PD is unclear. In this thesis, I describe the setup of a high content mitophagy siRNA screen to evaluate the functional role of prioritised PD risk genes. This screen identified two novel regulators of mitophagy, KAT8 and KANSL1, part of a protein complex involved in lysine acetylation. KAT8 and KANSL1 modulate PINK1 activity and subsequent mitophagy, linking sporadic and familial PD and providing a novel pathway for therapeutic investigation. Finally, I describe the optimisation of iPSC-derived neuron and iNeuron models to study mitophagy in more physiological systems. This includes the optimisation of CRISPR interference in the iNeuron model to modulate the levels of KAT8 and KANSL1 and investigate their role in regulating mitophagy in neuronal cells.

Download activity - last month

Export as JSONXMLCSV

Download activity - last 12 months

Export as JSONXMLCSV

Downloads by country - last 12 months

Export as XMLJSONCSV

Archive Staff Only

View Item