SQSTM1/p62 Expression Effects on Mitochondria and Protection from Neurodegeneration: A Proposed Role from Mitochondrial Dynamics to Learning and Memory
Type of Degreedissertation
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Sequestosome 1(SQSTM1/p62) is a multi-domain scaffolding protein involved in multiple cellular processes ranging from endocytosis to protein degradation that employ both the ubiquitin proteasome system and autophagy. In its role as a degradation pathway regulator, p62 has been localized to the mitochondria where is participates in mitophagy. The aforementioned roles of p62 all share one attribute, namely stress, which when applied to the cell drives multiple survival pathways. Conversely, the question of a physiological role for p62 at the mitochondria has not been addressed. By using innovative cell culture techniques to isolated hippocampal neurons from mouse brain, I have shown that p62 does participate in physiological mitochondrial function. I identify for the first time that p62 localization plays a role in regulating mitochondrial morphology, genome integrity and mitochondrial import of a key transcription factor, as well as, present evidence that these responses to the presence of p62 extend beyond the protein’s immediate influence on membrane potential. Changes in mitochondrial function have been associated with Affective spectrum and anxiety disorders. I report on the generation of a transgenic mouse overexpressing SQSTM1/p62 or a single point mutant (P392L) in the UBA domain of SQSTM1/p62. Mitochondrial energy output and functionality is improved in the overexpressing mouse compared to Wild Type. These elevated levels of mitochondrial functionality correlate directly with discernible improvements in mouse behaviors related to affective spectrum and anxiety disorders. I iii also describe how overexpression of SQSTM1/p62 improves spatial learning and long term memory formation in these transgenic mice. Thus, proteins that affect mitochondrial energetics and function could prove to be attractive targets for drug treatment for the psychiatric behavioral disorders. The results presented here suggest that SQSTM1/p62 provides an attractive target for therapeutic agents potentially suitable for the treatment of anxiety and affective spectrum disorders.