title: Autophagy alleviates neurodegeneration caused by mild impairment of oxidative metabolism.
abstract: Thiamine deficiency (TD) causes mild impairment of oxidative metabolism and region-selective neuronal loss in the brain, which may be mediated by neuronal oxidative stress, endoplasmic reticulum (ER) stress, and neuroinflammation. TD-induced brain damage is used to model neurodegenerative disorders, and the mechanism for the neuronal death is still unclear. We hypothesized that autophagy might be activated in the TD brain and play a protective role in TD-induced neuronal death. Our results demonstrated that TD induced the accumulation of autophagosomes in thalamic neurons measured by transmission electron microscopy, and the up-regulation of autophagic markers LC3-II, Atg5, and Beclin1 as measured with western blotting. TD also increased the expression of autophagic markers and induced LC3 puncta in SH-SY5Y neuroblastoma cells. TD-induced expression of autophagic markers was reversed once thiamine was re-administered. Both inhibition of autophagy by wortmannin and Beclin1 siRNA potentiated TD-induced death of SH-SY5Y cells. In contrast, activation of autophagy by rapamycin alleviated cell death induced by TD. Intraperitoneal injection of rapamycin stimulated neuronal autophagy and attenuated TD-induced neuronal death and microglia activation in the submedial thalamus nucleus (SmTN). TD inhibited the phosphorylation of p70S6 kinase, suggesting mTOR/p70S6 kinase pathway was involved in the TD-induced autophagy. These results suggest that autophagy is neuroprotective in response to TD-induced neuronal death in the central nervous system. This opens a potential therapeutic avenue for neurodegenerative diseases caused by mild impairment of oxidative metabolism. Autophagy is neuroprotective in response to thiamine deficiency (TD)-induced neuronal death. TD caused neuronal damage and induced the formation of autophagosome, and increased the expression of autophagy-related proteins. Autophagy sequestered damaged and dysfunctional organelles/protein, and transported them to lysosomes for degradation/recycling. This process provided nutrients for injured neurons. Wortmannin and knockdown of Beclin1 inhibited autophagy, and exacerbated TD-induced cell death, while activation of autophagy by rapamycin offered protection against TD neurotoxicity.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Meng
authors.forename: Yue
authors.initials: Y
authors.lastname: Yong
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Hanqing
authors.initials: H
authors.lastname: Ding
authors.forename: Zhiqin
authors.initials: Z
authors.lastname: Fan
authors.forename: Yifen
authors.initials: Y
authors.lastname: Tang
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
authors.forename: Zun-Ji
authors.initials: ZJ
authors.lastname: Ke
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D015536:Down-Regulation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000473:pathology*; D010084:Oxidation-Reduction; D010588:Phagosomes / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020123:Sirolimus / Q000633:toxicity; D013788:Thalamus / Q000166:cytology / Q000378:metabolism; D014162:Transfection; D014617:Vacuoles / Q000378:metabolism; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000900:Anti-Bacterial Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D020123:Sirolimus; D000077191:Wortmannin
keywords: autophagy; neurodegeneration; oxidative stress; thalamus; vitamin B1