The Impact of Mitochondrial Dysfunction on Neurogenesis and Neurodegeneration

Abstract

Neurogenesis is a tightly regulated process that occurs during embryonic development and throughout life in specific brain regions that include the subventricular zone (SVZ) of the lateral wall of the ventricle and the subgranular zone (SGZ) of the dentate gyrus of the hippocampus. A decline in neurogenesis is observed with aging and in several neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). It is therefore imperative to investigate the mechanisms involved in neurogenesis in order to identify therapeutic targets in neurodegeneration. In this dissertation, we identified early postnatal defects in neurogenesis in the 3xTg mouse model of AD well before the onset of amyloid β (Aβ) aggregation and cognitive decline. The neurogenesis defect observed was accompanied by mitochondrial dysfunction. We then proceeded to show that mitochondrial dynamics regulates neural stem cell (NSC) activation, proliferation, and differentiation in the adult SGZ brain and that altering dynamics with OPA1 knock out leads to learning and memory deficits. We identified the integrated stress response (ISR) pathway along with ATF4 and its downstream target Slc7a11 as major players in adapting to stress under mitochondrial dysfunction and probable therapeutic targets in neurodegeneration. While adult neurogenesis is believed to contribute to the repair of brain damage, neuroplasticity, and memory consolidation, the preservation of neurons is also important. For this reason, we determined whether similar mechanisms identified in NSCs play an important role in maintaining neuronal function and differentiation. Indeed, our findings showed that the knock down of OPA1 in neurons leads to the activation of ATF4 which in turn regulates neuron differentiation and adaption to stress. In addition, we reported that ATF4 has the potential to alter neuronal gene expression through binding and modulation of chromatin accessibility. Thus, we showed in this dissertation that mitochondrial dynamics play a central role in neurogenic fate decision and that the process is partially regulated by ATF4 which could be used as a target in neurodegenerative diseases.