Autophagy alleviates neurodegeneration caused by mild impairment of oxidative metabolism
Article first published online: 9 JUN 2013
© 2013 International Society for Neurochemistry
Journal of Neurochemistry
Volume 126, Issue 6, pages 805–818, September 2013
How to Cite
J. Neurochem. (2013) 126, 805–818.
- Issue published online: 6 SEP 2013
- Article first published online: 9 JUN 2013
- Accepted manuscript online: 15 APR 2013 07:30AM EST
- Manuscript Accepted: 11 APR 2013
- Manuscript Revised: 10 APR 2013
- Manuscript Received: 15 MAR 2013
- Ministry of Science and Technology of China. Grant Numbers: 2010CB912000, 2007CB947100
- National Natural Science Foundation of China. Grant Numbers: 31271142, 30870812
- Chinese Academy of Sciences. Grant Numbers: SIBS2008006, KSCX2-EW-R-08
- Institute for Nutritional Sciences and Xuhui Central Hospital. Grant Number: CRC20100010
- NIH/NIAAA. Grant Numbers: AA015407, AA019693
- oxidative stress;
- vitamin B1
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.