期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 18, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/ijms18030545
关键词
3-nitropropionic acid; p62; reactive oxygen species; sestrin2; sulfiredoxin
资金
- Ministry of Science and Technology (MOST) in Taiwan [MOST 103-2314-B-010-013-MY3, MOST 104-2314-B-010-014-MY2]
- Ministry of Education in Taiwan-Aim for the Top University Plan [105AC-B5]
- Department of Health in Taipei City Government [10501-62-050, 10601-62-003]
- Chang Gung Memorial Hospital, Kaohsiung, Taiwan [CMRPG8C1221, CMRPG8C1222, CMRPG8C1223]
- MOST in Taiwan [MOST 104-2811-B-010-035]
In addition to its well-established neurotrophic action, brain-derived neurotrophic factor (BDNF) also possesses other neuroprotective effects including anti-apoptosis, anti-oxidation, and suppression of autophagy. We have shown before that BDNF triggers multiple mechanisms to confer neuronal resistance against 3-nitropropionic acid (3-NP)-induced mitochondrial dysfunction in primary rat cortical cultures. The beneficial effects of BDNF involve the induction of anti-oxidative thioredoxin with the resultant expression of anti-apoptotic B-cell lymphoma 2 (Bcl-2) as well as erythropoietin (EPO)-dependent stimulation of sonic hedgehog (SHH). We further revealed that BDNF may bring the expression of sulfiredoxin, an ATP-dependent antioxidant enzyme, to offset mitochondrial inhibition in cortical neurons. Recently, we provided insights into another novel anti-oxidative mechanism of BDNF, which involves the augmentation of sestrin2 expression to endow neuronal resistance against oxidative stress induced by 3-NP; BDNF induction of sestrin2 entails the activation of a pathway involving nitric oxide (NO), cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG), and nuclear factor-kappa B (NF-kappa B). Apart from anti-apoptosis and anti-oxidation, we demonstrated in our most recent study that BDNF may activate the mammalian target of rapamycin (mTOR) with resultant activation of transcription factor c-Jun, thereby stimulating the expression of p62/sequestosome-1 to suppress heightened autophagy as a result of 3-NP exposure. Together, our results provide in-depth insight into multi-faceted protective mechanisms of BDNF against mitochondrial dysfunction commonly associated with the pathogenesis of many chronic neurodegenerative disorders. Delineation of the protective signaling pathways elicited by BDNF would endow a rationale to develop novel therapeutic regimens to halt or prevent the progression of neurodegeneration.
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