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Autophagy alleviates neurodegeneration caused by mild impairment of oxidative metabolism.
J Neurochem. 2013 Sep; 126(6):805-18.JN

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+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23586593

Citation

Meng, Ya, et al. "Autophagy Alleviates Neurodegeneration Caused By Mild Impairment of Oxidative Metabolism." Journal of Neurochemistry, vol. 126, no. 6, 2013, pp. 805-18.
Meng Y, Yong Y, Yang G, et al. Autophagy alleviates neurodegeneration caused by mild impairment of oxidative metabolism. J Neurochem. 2013;126(6):805-18.
Meng, Y., Yong, Y., Yang, G., Ding, H., Fan, Z., Tang, Y., Luo, J., & Ke, Z. J. (2013). Autophagy alleviates neurodegeneration caused by mild impairment of oxidative metabolism. Journal of Neurochemistry, 126(6), 805-18. https://doi.org/10.1111/jnc.12268
Meng Y, et al. Autophagy Alleviates Neurodegeneration Caused By Mild Impairment of Oxidative Metabolism. J Neurochem. 2013;126(6):805-18. PubMed PMID: 23586593.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Autophagy alleviates neurodegeneration caused by mild impairment of oxidative metabolism. AU - Meng,Ya, AU - Yong,Yue, AU - Yang,Guang, AU - Ding,Hanqing, AU - Fan,Zhiqin, AU - Tang,Yifen, AU - Luo,Jia, AU - Ke,Zun-Ji, Y1 - 2013/06/09/ PY - 2013/03/15/received PY - 2013/04/10/revised PY - 2013/04/11/accepted PY - 2013/4/17/entrez PY - 2013/4/17/pubmed PY - 2013/11/1/medline KW - autophagy KW - neurodegeneration KW - oxidative stress KW - thalamus KW - vitamin B1 SP - 805 EP - 18 JF - Journal of neurochemistry JO - J Neurochem VL - 126 IS - 6 N2 - 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. SN - 1471-4159 UR - https://www.unboundmedicine.com/medline/citation/23586593/Autophagy_alleviates_neurodegeneration_caused_by_mild_impairment_of_oxidative_metabolism_ L2 - https://doi.org/10.1111/jnc.12268 DB - PRIME DP - Unbound Medicine ER -