Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons

SUMMARY Autophagy defects have been implicated in multiple late-onset neurodegenerative diseases. Since aging is the most common risk factor in neurodegeneration, we asked how autophagy is modulated in aging neurons. We compared the dynamics of autophagosome biogenesis in neurons from young adult and aged mice, identifying a significant decrease in biogenesis during aging. Autophagosome assembly kinetics are disrupted, with frequent production of stalled isolation membranes in neurons from aged mice; these precursors failed to resolve into LC3-positive autophagosomes. We did not detect alterations in the initial induction/nucleation steps of autophagosome formation. However, we found that the transmembrane protein Atg9 remained aberrantly associated with stalled isolation membranes, suggesting a specific disruption in the WIPI-dependent retrieval of Atg9. Depletion of WIPI2 from young neurons was sufficient to induce a similar deficit. Further, exogenous expression of WIPI2 in neurons from aged mice was sufficient to restore autophagosome biogenesis to the rates seen in neurons from young adult mice, suggesting a novel therapeutic target for age-associated neurodegeneration.