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.
Highlights
Aging is a complex process that often impairs physiological and tissue function
Since impaired autophagy has been implicated in the pathogenesis of neurodegeneration and age is the most relevant risk factor for neurodegenerative disease, we used the GFP-LC3B probe to assess how biogenesis rates change with age in primary dorsal root ganglion (DRG) neurons dissected from mice of four different ages: 1-month-old young mice, 3-month-old young adult mice, 16–17 month-old aged mice, and 24month-old advanced aged mice
WIPI2B overexpression in neurons from aged mice increased the rate of autophagosome biogenesis, restoring this rate to that found in neurons from young adult mice
Summary
Aging is a complex process that often impairs physiological and tissue function. Age is the most relevant risk factor for many prominent diseases and disorders, including cancers and neurodegenerative diseases (Niccoli and Partridge, 2012). The autophagy pathway has been directly implicated in aging in model organisms (Cuervo, 2008; Rubinsztein et al, 2011). Neurons are post-mitotic, terminally differentiated cells that must maintain function in distal compartments throughout the lifetime of a human. These maintenance mechanisms may wane as a person ages, potentially contributing to neuronal dysfunction and death. Disrupting autophagy in neurons results in neurodegeneration in animal models (Hara et al, 2006; Komatsu et al, 2006; Zhao et al, 2013)
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