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Glycogen synthase protects neurons from cytotoxicity of mutant huntingtin by enhancing the autophagy flux
| Content Provider | Semantic Scholar |
|---|---|
| Author | Rai, Anupama Singh, Pankaj Kumar Singh, Virender Kumar, Vipendra Mishra, Ravi Krishna Thakur, Ashwani Kumar Mahadevan, Anita Shankar, Susarla Krishna Jana, Nihar R. Ganesh, Subramaniam |
| Copyright Year | 2017 |
| Abstract | Healthy neurons do not store glycogen while they do possess the machinery for the glycogen synthesis albeit at an inactive state. Neurons in the degenerating brain, however, are known to accumulate glycogen, although its significance was not well understood. Emerging reports present contrasting views on neuronal glycogen synthesis; a few reports demonstrate a neurotoxic effect of glycogen while a few others suggest glycogen to be neuroprotective. Thus, the specific role of glycogen and glycogen synthase in neuronal physiology is largely unexplored. Using cellular and animal models of Huntington’s disease, we show here that the overexpression of cytotoxic mutant huntingtin protein induces glycogen synthesis in the neurons by activating glycogen synthase and the overexpressed glycogen synthase protected neurons from the cytotoxicity of the mutant huntingtin. Exposure of neuronal cells to proteasomal blockade and oxidative stress also activate glycogen synthase to induce glycogen synthesis and to protect against stress-induced neuronal death. We show that the glycogen synthase plays an essential and inductive role in the neuronal autophagic flux, and helps in clearing the cytotoxic huntingtin aggregate. We also show that the increased neuronal glycogen inhibits the aggregation of mutant huntingtin, and thus could directly contribute to its clearance. Finally, we demonstrate that excessive autophagy flux is the molecular basis of cell death caused by the activation of glycogen synthase in unstressed neurons. Taken together, our results thus provide a novel function for glycogen synthase in proteolytic processes and offer insight into the role of glycogen synthase and glycogen in both survival and death of the neurons. |
| Starting Page | 537 |
| Ending Page | 552 |
| Page Count | 16 |
| File Format | PDF HTM / HTML |
| PubMed reference number | 29422655v1 |
| Alternate Webpage(s) | https://doi.org/10.1038/s41419-017-0190-5 |
| DOI | 10.1038/s41419-017-0190-5 |
| Journal | Cell Death & Disease |
| Volume Number | 9 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | 3-Phosphoshikimate 1-carboxyvinyltransferase Abnormal degeneration Activation action Animal Model Autophagy Cell Death Cessation of life Flux Glycogen (Starch) Synthase Glycogen Storage Disease HD protein, human HTT gene Huntingtin Protein Nerve Degeneration Neurotoxicity Syndromes Oxidative Stress Paget's Disease, Mammary Physical Inactivity glycogen biosynthetic process physiological aspects |
| Content Type | Text |
| Resource Type | Article |
