Regulation of Autophagic Cell Death in Neurons

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DESCRIPTION (provided by applicant): Human post mortem brain tissue from patients with Parkinson's, Alzheimer's and Huntington's disease demonstrate signs of increased autophagy (Cataldo et al., 1996; Anglade et al., 1997; Kegel et al.,2000; Nixon et al.,2000). Autophagy is a tightly controlled survival response activated in nutrient deprived cells as a means for recycling nutrients (e.g.nucleotides and amino acids) back to the cell (Levine and Yuan, 2005). However, deregulation of the autophagic pathway may contribute to the pathogenesis of neurodegenerative diseases (Nixon, 2006; Martinez-Vicente and Cuervo, 2007). Furthermore, it is possible that pro-death signals like Fas stimulate autophagy, which accelerates this process resulting in enhanced apoptotic and autophagic- induced neuronal death (Levine and Yuan, 2005). The cell signaling events that switch autophagy from a neuroprotective to a detrimental response are under active investigation. Therapies aimed at controlling the autophagic response during neurodegeneration may slow the progression of neuronal loss allowing for the recovery and repair of damaged neurons. Indeed, neurotrophic factors have been shown to regulate autophagy. Preliminary data from our lab demonstrates that IGF-1 reduces the accumulation of large autophagic vacuoles and inhibits autophagic-mediated death of cerebellar purkinje neurons. We hypothesize that IGF-1inhibits autophagic-induced cell death of cerebellar Purkinje neurons not by blocking formation of autophagic vesicles, but rather by accelerating autophagic flux, thus allowing for faster recycling of amino acids and recovery in trophic factor deprived cells. The first aim of this proposal will determine whether IGF-1 regulates autophagic vacuole formation, accumulation and/or fusion with the lysosome. The second aim will address whether IGF-1 effects flux through the autophagic pathway to increase autophagy efficiency. The third specific aim will begin to address the mechanism of IGF-1action and investigate a'potential novel role for GSK-3beta in the regulation of autophagy. Understanding the molecular mechanisms that control autophagic cell death in these neurons and how neurotrophic factors regulate autophagy may form a rationale basis for the design of new therapeutic strategies for neurodegeneration.