One of the major challenges for the U.S. Department of Veterans Affairs is to extend the health-span of the veterans and their families as their physical and/or cognitive performance capabilities decline with age. Human neurodegenerative protein misfolding disorders or proteinopathies, are associated with abnormal protein depositions in brain neurons. They include polyglutamine (polyQ) disorders such as Huntington's disease and α-synucleinopathies such as Parkinson's disease. Disclosing the basic molecular and metabolic alterations that occur during aging of post-mitotic cells such as neurons, under proteotoxic stress is crucial for understanding the etiology of neuro-proteinopathies. Metabolic and mitochondrial alterations are hallmarks of aging and neurodegeneration. Over the last decade, we and others have shown that enhancement of mitogenesis or overexpression of NMNAT/NMA1, an enzyme in the Nicotinic acid/Nicotinamide Salvage NAD+ biosynthetic pathway, act as powerful suppressor of proteotoxicities in yeast, fly and mouse models. Through screens in yeast models we identified three additional enzymes of the NAD+ biosynthetic salvage pathway with a role in proteostasis: NADS/Qns1, NaPTRase/Npt1 and NDase/Pnc1. Our observations suggest the existence of an evolutionarily conserved strategy of `repurposing' (or `moonlighting') housekeeping enzymes under stress conditions. Under proteotoxic stress, the four proteins are recruited as molecular chaperones with holdase and foldase activities. In yeast cells, the NAD+ salvage proteins act by preventing misfolding and, together with the Hsp90 chaperone, promoting the refolding of extended polyQ domains or α-synuclein. Their catalytic function is not required for their chaperone role. Preliminary studies in human neuronal models of HD have shown that the human proteins conserve similar “moonlighting” functions and the capacity to protect against proteotoxic stress. We now propose to address the fundamental problem of the intricate interaction between metabolic and cellular protein homeostasis pathways in human neurons. Some of our studies will continue exploiting the yeast model to perform structure-function relationship studies to disclose the domains involved in the chaperone function of the four yeast proteins. We will also continue using yeast models of HD to screen for suppressors among the Nicotinamide Riboside Salvage NAD+ biosynthetic pathway enzymes. An essential component of our studies is the translation of the results previously obtained in yeast to HD patient-derived neurons and HD mouse models. Two neuronal culture systems will be used to test different aspects of disease progression: HD patient-derived induced pluripotent stem cells (iPSCs) differentiated into neurons and HD patient-derived neurons through direct conversion of fibroblasts. A mouse model expressing full-length huntingtin will be used for pre-clinical efficacy studies in vivo. We hypothesize that mitochondrial biogenesis-...