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.
Highlights
Neurotrophic factors are critical ligands for neuronal cells to proliferate, differentiate, and grow during developmental stages and play important roles to maintain survival, network connectivity, and neuronal plasticity in adult brains
We further demonstrated that brain-derived neurotrophic factor (BDNF)-mediated 3-nitropropionic acid (3-NP) resistance in cortical neurons counts on the effects of sonic hedgehog (SHH), a mammalian member of the hedgehog family which regulates the polarity of the central nervous system as well as proliferation, self-renewal, and survival of neuronal cells [29]
During investigation of the BDNF effects on activation of c-Jun N-terminal kinases (JNKs) and their downstream target c-Jun, we found that BDNF substantially enhances the expression of c-Jun without inducing JNK phosphorylation [32]. c-Jun is a well-known component of the activator protein 1 (AP-1) transcription factor complex
Summary
Neurotrophic factors are critical ligands for neuronal cells to proliferate, differentiate, and grow during developmental stages and play important roles to maintain survival, network connectivity, and neuronal plasticity in adult brains. We briefly introduce the recent advance in the molecular mechanisms of the BDNF-mediated protective effects against neuronal dysfunction induced by 3-NP, including our previous studies [19].
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