Kelly, Katie; (2024) A Bioinformatic and Biological Investigation of the Relationship Between OGT and PINK1-Dependent Mitophagy, in the Context of Parkinson’s Disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Whilst the majority of Parkinson’s disease (PD) cases are sporadic, much of our under- standing of the pathophysiological basis of disease can be traced back to the study of rare, monogenic forms. A PINK1-mitophagy screen has provided a functional link between the chromatin remodeling Non-specific lethal (NSL) complex, a mediator of PD risk, and PD. Yet, the mechanistic basis of this link is unknown. This thesis has taken a dual bioin- formatic/biological approach to: i) explore the functional relevance of the NSL complex to PD and, ii) to explore the role of NSL complex member O-GlcNAc Transferase (OGT) in the regulation of PINK1-mitophagy. This thesis aims to shed light on the upstream regulatory mechanisms governing PINK1-mitophagy, a pathway bridging sporadic and familial forms of the disease. First, a protein interaction network has been built around the NSL complex in a weighted protein-protein interaction network analysis (W-PPI-NA). This has revealed the NSL/PD link to be underpinned at the protein level by both the mitochondrial and nuclear functionality of the complex. Following from this observation, OGT has been prioritised for functional studies in SH SY5Y neuroblastoma cells and identified as a negative regu- lator of PINK1-mitophagy via regulation of PINK1 at the level of transcription. TRAK1, a substrate of OGT has then been prioritised bioinformatically and proposed as a mediator of the OGT KD clearance effect. This interaction has suggested a mechanistic link be- tween mitochondrial motility and PINK1-mitophagy. Finally, genetic depletion of OGT and TRAK1 in hiPSC-derived i3Neurons has indicated that the role of both proteins in PINK1-mitophagy may be more complex in neuronal cells, or cell-type specific. However, conservation of a genetic relationship between OGT and PINK within the i3Neurons points to a functional association within this cell type. In conclusion, these findings strengthen the link between the NSL complex and PINK1-mitophagy, illuminating OGT as a possible mediator of this link.

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