title: More Insight into BDNF against Neurodegeneration: Anti-Apoptosis, Anti-Oxidation, and Suppression of Autophagy.
abstract: 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-κB (NF-κB). 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.
authors.affiliation: Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan. chensd@adm.cgmh.org.tw.|Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan. chensd@adm.cgmh.org.tw.|College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan. chensd@adm.cgmh.org.tw.
authors.forename: Shang-Der
authors.initials: SD
authors.lastname: Chen
authors.affiliation: Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 11221, Taiwan. ta730112@hotmail.com.|Institute of Brain Science and Brain Research Center, National Yang-Ming University, Taipei 11221, Taiwan. ta730112@hotmail.com.
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Wu
authors.affiliation: Department of Neurology, Taipei City Hospital, Taipei 11221, Taiwan. huangshiaowei@gmail.com.
authors.forename: Wei-Chao
authors.initials: WC
authors.lastname: Hwang
authors.affiliation: Institute of Brain Science and Brain Research Center, National Yang-Ming University, Taipei 11221, Taiwan. diyang@ym.edu.tw.
authors.forename: Ding-I
authors.initials: DI
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009574:Nitro Compounds / Q000494:pharmacology / Q000633:toxicity; D009687:Nuclear Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology / Q000633:toxicity; D016601:RNA-Binding Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000084622:Sestrins
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D009574:Nitro Compounds; D009687:Nuclear Proteins; D011422:Propionates; D016601:RNA-Binding Proteins; C118585:P62 protein, human; C465398:SESN2 protein, human; D000084622:Sestrins; C015392:3-nitropropionic acid
keywords: 3-nitropropionic acid; p62; reactive oxygen species; sestrin2; sulfiredoxin