Neuronal autophagy declines substantially with age and is rescued by overexpression of WIPI2

Macroautophagy/autophagy is implicated in age-dependent neurodegenerative diseases, including amyotrophic lateral sclerosis and Parkinson, Huntington and Alzheimer diseases, suggesting that an age-related decline in neuronal autophagy may contribute to the onset of neurodegeneration. We identified a significant decline in the rate of axonal autophagosome formation in neurons cultured from aged mice, accompanied by a striking increase in the accumulation of autophagic structures with aberrant morphologies. Using live-cell microscopy, we identified the specific step in autophagosome formation that becomes impaired with age, focusing on the role of the phosphoinositide binding protein WIPI2. We determined that the dynamic and local phosphorylation of WIPI2 is a critical regulatory step in autophagosome biogenesis in neurons and that this step is specifically affected by aging. Together, these results provide new insights into the regulation of autophagosome biogenesis in neurons and delineate how autophagosome formation is affected by age. These observations also point to a potential new target for therapeutic intervention.