Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons
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 mammalia...
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doaj-13a886887e1f4f9592f816d0d5cc115f2021-05-05T17:46:27ZengeLife Sciences Publications LtdeLife2050-084X2019-07-01810.7554/eLife.44219Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neuronsAndrea KH Stavoe0https://orcid.org/0000-0002-4073-4565Pallavi P Gopal1Andrea Gubas2Sharon A Tooze3Erika LF Holzbaur4https://orcid.org/0000-0001-5389-4114Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesDepartment of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesMolecular Cell Biology of Autophagy Laboratory, The Francis Crick Institute, London, United KingdomMolecular Cell Biology of Autophagy Laboratory, The Francis Crick Institute, London, United KingdomDepartment of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United StatesAutophagy 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.https://elifesciences.org/articles/44219autophagyagingautophagosome biogenesisneuronsWIPI2B |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Andrea KH Stavoe Pallavi P Gopal Andrea Gubas Sharon A Tooze Erika LF Holzbaur |
spellingShingle |
Andrea KH Stavoe Pallavi P Gopal Andrea Gubas Sharon A Tooze Erika LF Holzbaur Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons eLife autophagy aging autophagosome biogenesis neurons WIPI2B |
author_facet |
Andrea KH Stavoe Pallavi P Gopal Andrea Gubas Sharon A Tooze Erika LF Holzbaur |
author_sort |
Andrea KH Stavoe |
title |
Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons |
title_short |
Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons |
title_full |
Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons |
title_fullStr |
Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons |
title_full_unstemmed |
Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons |
title_sort |
expression of wipi2b counteracts age-related decline in autophagosome biogenesis in neurons |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2019-07-01 |
description |
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. |
topic |
autophagy aging autophagosome biogenesis neurons WIPI2B |
url |
https://elifesciences.org/articles/44219 |
work_keys_str_mv |
AT andreakhstavoe expressionofwipi2bcounteractsagerelateddeclineinautophagosomebiogenesisinneurons AT pallavipgopal expressionofwipi2bcounteractsagerelateddeclineinautophagosomebiogenesisinneurons AT andreagubas expressionofwipi2bcounteractsagerelateddeclineinautophagosomebiogenesisinneurons AT sharonatooze expressionofwipi2bcounteractsagerelateddeclineinautophagosomebiogenesisinneurons AT erikalfholzbaur expressionofwipi2bcounteractsagerelateddeclineinautophagosomebiogenesisinneurons |
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1721458940550578176 |