10779/crick.11559546.v1
Andrea KH Stavoe
Andrea KH
Stavoe
Pallavi P Gopal
Pallavi P
Gopal
Andrea Gubas
Andrea
Gubas
Sharon A Tooze
Sharon A
Tooze
Erika LF Holzbaur
Erika LF
Holzbaur
Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons.
The Francis Crick Institute
2020
WIPI2B
aging
autophagosome biogenesis
autophagy
cell biology
mouse
neurons
neuroscience
Aging
Animals
Autophagosomes
Autophagy
Gene Expression
Mice
Neurons
Tooze FC001187
0601 Biochemistry and Cell Biology
2020-01-09 16:43:14
Journal contribution
https://crick.figshare.com/articles/journal_contribution/Expression_of_WIPI2B_counteracts_age-related_decline_in_autophagosome_biogenesis_in_neurons_/11559546
Autophagy defects are implicated in multiple late-onset neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS) and Alzheimer's, Huntington's, and Parkinson's diseases. Since aging is the most common shared risk factor in neurodegeneration, we assessed rates of autophagy in mammalian neurons during aging. We identified a significant decrease in the rate of constitutive autophagosome biogenesis during aging and observed pronounced morphological defects in autophagosomes in neurons from aged mice. While early stages of autophagosome formation were unaffected, we detected the frequent production of stalled LC3B-negative isolation membranes in neurons from aged mice. These stalled structures recruited the majority of the autophagy machinery, but failed to develop into LC3B-positive autophagosomes. Importantly, ectopically expressing WIPI2B effectively restored autophagosome biogenesis in aged neurons. This rescue is dependent on the phosphorylation state of WIPI2B at the isolation membrane, suggesting a novel therapeutic target in age-associated neurodegeneration.