Circadian control of BDNF-mediated Nrf2 activation in astrocytes protects dopaminergic neurons from ferroptosis

TY - JOUR

T1 - Circadian control of BDNF-mediated Nrf2 activation in astrocytes protects dopaminergic neurons from ferroptosis

AU - Ishii, Tetsuro

AU - Warabi, Eiji

AU - Mann, Giovanni E

PY - 2018/9/4

Y1 - 2018/9/4

N2 - Astrocyte-neuron interactions protect neurons from iron-mediated toxicity. As dopamine can be metabolized to reactive quinones, dopaminergic neurons are susceptible to oxidative damage and ferroptosis-like induced cell death. Detoxification enzymes are required to protect neurons. Brain-derived neurotrophic factor (BDNF) plays a key role in the regulation of redox sensitive transcription factor Nrf2 in astrocytes and metabolic cooperation between astrocytes and neurons. This article reviews the importance of BDNF and astrocyte-neuron interactions in the protection of neurons against oxidative damages in rodent brains. We previously proposed that BDNF activates Nrf2 via the truncated TrkB.T1 and p75NTR receptor complex in astrocytes. Stimulation by BDNF generates the signaling molecule ceramide, which activates PKCζ leading to induction of the CK2-Nrf2 signaling axis. As a cell clock regulates p75NTR expression, we suggested that BDNF effectively activates Nrf2 in astrocytes during the rest phase. In contrast, neurons express both TrkB.FL and TrkB.T1, and TrkB.FL tyrosine kinase activity inhibits p75NTR-dependent ceramide generation and internalizes p75NTR. Therefore, BDNF may not effectively activate Nrf2 in neurons. Notably, neurons only weakly activate detoxification and antioxidant enzymes/proteins via the Nrf2-ARE signaling axis. Thus, astrocytes may provide relevant transcripts and/or proteins to neurons via microparticles/exosomes increasing neuronal resistance to oxidative stress. Circadian increases in the levels of circulating glucocorticoids may further facilitate material transfer from astrocytes to neurons via the stimulation of pannexin 1 channels-P2X7R signaling pathway in astrocytes at the beginning of the active phase. Dysregulation of astrocyte-neuron interactions could therefore contribute to the pathogenesis of neurodegenerative diseases including Parkinson’s disease.

AB - Astrocyte-neuron interactions protect neurons from iron-mediated toxicity. As dopamine can be metabolized to reactive quinones, dopaminergic neurons are susceptible to oxidative damage and ferroptosis-like induced cell death. Detoxification enzymes are required to protect neurons. Brain-derived neurotrophic factor (BDNF) plays a key role in the regulation of redox sensitive transcription factor Nrf2 in astrocytes and metabolic cooperation between astrocytes and neurons. This article reviews the importance of BDNF and astrocyte-neuron interactions in the protection of neurons against oxidative damages in rodent brains. We previously proposed that BDNF activates Nrf2 via the truncated TrkB.T1 and p75NTR receptor complex in astrocytes. Stimulation by BDNF generates the signaling molecule ceramide, which activates PKCζ leading to induction of the CK2-Nrf2 signaling axis. As a cell clock regulates p75NTR expression, we suggested that BDNF effectively activates Nrf2 in astrocytes during the rest phase. In contrast, neurons express both TrkB.FL and TrkB.T1, and TrkB.FL tyrosine kinase activity inhibits p75NTR-dependent ceramide generation and internalizes p75NTR. Therefore, BDNF may not effectively activate Nrf2 in neurons. Notably, neurons only weakly activate detoxification and antioxidant enzymes/proteins via the Nrf2-ARE signaling axis. Thus, astrocytes may provide relevant transcripts and/or proteins to neurons via microparticles/exosomes increasing neuronal resistance to oxidative stress. Circadian increases in the levels of circulating glucocorticoids may further facilitate material transfer from astrocytes to neurons via the stimulation of pannexin 1 channels-P2X7R signaling pathway in astrocytes at the beginning of the active phase. Dysregulation of astrocyte-neuron interactions could therefore contribute to the pathogenesis of neurodegenerative diseases including Parkinson’s disease.

KW - ferroptosis

KW - dopamine

KW - Nrf2

KW - BDNF

KW - circadian rhythm

KW - TrkB

KW - p75

KW - cystine transport

KW - GSH

KW - mitochondria

KW - CK2

KW - PKA

KW - Parkinson’s disease

U2 - 10.1016/j.freeradbiomed.2018.09.002

DO - 10.1016/j.freeradbiomed.2018.09.002

M3 - Article

SN - 0891-5849

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

ER -