Jul 17, 2019

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

ELife
Andrea K H StavoeErika L F Holzbaur

Abstract

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.

  • References102
  • Citations3

Mentioned in this Paper

Membrane
Isolation Aspects
Nerve Degeneration
Alzheimer's Disease
Amyotrophic Lateral Sclerosis
Autophagic Vacuole Assembly
Structure
Aging
Parkinson Disease
Huntington Disease

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