The central premise of this exploratory R21 application is to understand endurance exercise-dependent mechanisms protecting against polyglutamine (polyQ) neurodegeneration. Nine age-related neurological disorders are caused by abnormal expansion of the CAG triplet repeat of their respective genes. The elongated CAG repeat encodes an abnormally long polyQ tract that causes neuronal dysfunction and degeneration. These diseases constitute the polyQ family, which includes Spinocerebellar Ataxias (SCAs) 1, 2, 3, 6, 7 and 17, Huntington's Disease, Kennedy's Disease and Dentatorubral-pallidolyusian atrophy. Currently, there is no therapeutic solution for any member of the polyQ family; all patients lose their ability to control movement over time, invariably becoming wheelchair-bound and experiencing impaired control of other body parts as well. Endurance exercise is proven to ameliorate disease conditions in various disease models across species. We recently investigated the potential impact of exercise on loss of mobility in Drosophila melanogaster models of three polyQ disorders, SCA2, SCA3 and SCA6. We reasoned that using the fruit fly would provide expedient, in vivo information about conserved molecular pathways and mechanisms that, once characterized and understood, can be subsequently explored and expanded in vertebrates. Excitingly, we found that daily exercise significantly and markedly preserved mobility and endurance in aging SCA flies, indicating impaired disease progression. Based on additional results, we found that improved motility coincided with reduced disease protein levels. Through this proposal, we seek to expand on these promising observations through two aims that will explore the protective role of exercise across the spectrum of polyQ diseases, and will define molecular mechanisms that can be mobilized therapeutically in polyQ disease patients.