Dynamic regulation of autophagy in neurons during synaptic plasticity and aging

University Of Pennsylvania, Philadelphia PA

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Abstract

Project Summary Neurodegenerative diseases have become enormous financial and societal burdens as human life expectancy has increased. Misregulation of autophagy has been implicated in neurodegenerative disorders, including Alzheimer?s Disease, Parkinson?s Disease and Huntington?s Disease. While many studies have elucidated autophagy and its role in cellular homeostasis in yeast and mammalian cell culture, much less in known about autophagy in neurons. Autophagosome biogenesis is known to occur at the distal tips of axons, and recent studies have indicated that presynaptic activity modulates autophagosome biogenesis. Our preliminary data suggests that autophagosome biogenesis and flux decrease with age in neurons. Our preliminary data further suggest that the kinetics of autophagosome assembly factors are disrupted in aged neurons compared to young neurons. We propose to uncover the temporal dynamics of autophagosome biogenesis, cargo uptake, maturation, trafficking, and acidification in neurons during aging. We will examine these changes in young and aged mice and compare wild type mice to mouse models of neurodegenerative diseases. Our studies will help us elucidate how aging modulates autophagy, which will further our understanding of how misregulation of autophagy leads to serious neurodegenerative diseases. Similarly, uncovering how autophagosome biogenesis is regulated during aging will be important for developing treatments for autophagy-related neurodegenerative diseases.