Master of Science
Autophagy is highly conserved cellular process that functions in ensuring the turnover of proteins and organelles in a number of different cell types. Mitophagy is a selective form of autophagy which serves to target and rid the cell of damaged or superfluous mitochondria. The process is central to preventing the accumulation of defective mitochondria and is particularly important in neurons, which rely exclusively on mitochondria to sustain their immense metabolic needs. Dysregulation of autophagy is believed to contribute to the neurodegeneration seen in such disorders as Parkinson’s disease and cerebral ischemia. However, further understanding of the role of neuronal autophagy under stress conditions, and the relevant players involved in this process is required. In recent years, two homologous proteins expressed only in higher eukaryotes have been described to play roles in mammalian autophagy and mitophagy. Tumour- protein 53-induced nuclear protein 2 (Tp53INP2) has a bi-functional role as a modulator of autophagy and gene transcription. This protein was shown to participate in non-neuronal autophagy, however its role in mitophagy is not well understood. Additionally, tumour- protein 53-induced nuclear protein 1 (Tp53INP1), has been suggested to play a role in autophagy as well as PINK1/Parkin mitophagy, however neither protein has been investigated in neuronal paradigms. Our findings demonstrate that cerebellar granule neurons and primary cortical neurons from Tp53INP1-/- mice demonstrate attenuated autophagy induction in response to trophic factor deprivation and hypoxic stress, respectively. We also demonstrate through confocal microscopy that Tp53INP2 responds to CCCP-induced mitochondrial stress by shuttling out of the nucleus and co-localizing with autophagosomal protein LC3, suggesting that it may play a role in mitophagy.
Shyam, Vidhyasree, "Investigating the Role of Tp53INP1 and Tp53INP2 in Neuronal Autophagy and Mitophagy" (2019). Electronic Thesis and Dissertation Repository. 6013.
Available for download on Monday, January 25, 2021