Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons
| Autor: | Andrea K.H. Stavoe, Erika L.F. Holzbaur, Sharon A. Tooze, Andrea Gubas, Pallavi P. Gopal |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Autophagosome Model organisms autophagy Aging autophagosome biogenesis Mouse QH301-705.5 Science Autophagy-Related Proteins Gene Expression Biology Biochemistry & Proteomics General Biochemistry Genetics and Molecular Biology 12. Responsible consumption Imaging 03 medical and health sciences Mice Signalling & Oncogenes 0302 clinical medicine WIPI2B Isolation membrane Age related medicine Animals Amyotrophic lateral sclerosis Biology (General) Neurons Chemical Biology & High Throughput General Immunology and Microbiology General Neuroscience Neurodegeneration Autophagy Autophagosomes General Medicine Cell Biology Phosphate-Binding Proteins medicine.disease Cell biology 030104 developmental biology Phosphorylation Medicine 030217 neurology & neurosurgery Biogenesis Research Article Neuroscience |
| Zdroj: | eLife eLife, Vol 8 (2019) |
| DOI: | 10.25418/crick.11559546.v1 |
| Popis: | 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. eLife digest Unlike most of the cells in our body, our neurons are as old as we are: while other cell types are replaced as they wear out, our neurons must last our entire lifetime. The symptoms of disorders such as Alzheimer's disease and ALS result from neurons in the brain or spinal cord degenerating or dying. But why do neurons sometimes die? One reason may be that elderly neurons struggle to remove waste products. Cells get rid of worn out or damaged components through a process called autophagy. A membranous structure known as the autophagosome engulfs waste materials, before it fuses with another structure, the lysosome, which contains enzymes that break down and recycle the waste. If any part of this process fails, waste products instead build up inside cells. This prevents the cells from working properly and eventually kills them. Aging is the major shared risk factor for many diseases in which brain cells slowly die. Could this be because autophagy becomes less effective with age? Stavoe et al. isolated neurons from young adult, aging and aged mice, and used live cell microscopy to follow autophagy in real time. The results determined that autophagy does indeed work less efficiently in elderly neurons. The reason is that the formation of the autophagosome stalls halfway through. However, increasing the amount of one specific protein, WIPI2B, rescues this defect and enables the cells to produce normal autophagosomes again. As long-lived cells, neurons depend on autophagy to stay healthy. Without this trash disposal system, neurons accumulate clumps of damaged proteins and eventually start to break down. The results of Stavoe et al. identify one way of overcoming this aging-related problem. As well as providing insights into neuronal biology, the results suggest a new therapeutic approach to be developed and tested in the future. |
| Databáze: | OpenAIRE |
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