Non‐canonical activation ofCREBmediates neuroprotection in aCaenorhabditis elegansmodel of excitotoxic necrosis

Abstract

Excitotoxicity, caused by exaggerated neuronal stimulation by Glutamate (Glu), is a major cause of neurodegeneration in brain ischemia. While we know that neurodegeneration is triggered by overstimulation of Glu‐receptors (GluRs), the subsequent mechanisms that lead to cellular demise remain controversial. Surprisingly, signaling downstream of GluRs can also activate neuroprotective pathways. The strongest evidence involves activation of the transcription factor cAMP response element‐binding protein (CREB), widely recognized for its importance in synaptic plasticity. Canonical views describe CREB as a phosphorylation‐triggered transcription factor, where transcriptional activation involves CREB phosphorylation and association with CREB‐binding protein. However, given CREB's ubiquitous cross‐tissue expression, the multitude of cascades leading to CREB phosphorylation, and its ability to regulate thousands of genes, it remains unclear how CREB exerts closely tailored, differential neuroprotective responses in excitotoxicity. A non‐canonical, alternative cascade for activation of CREB‐mediated transcription involves the CREB co‐factor cAMP‐regulated transcriptional co‐activator (CRTC), and may be independent of CREB phosphorylation. To identify cascades that activate CREB in excitotoxicity we used a Caenorhabditis elegans model of neurodegeneration by excitotoxic necrosis. We demonstrated that CREB's neuroprotective effect was conserved, and seemed most effective in neurons with moderate Glu exposure. We found that factors mediating canonical CREB activation were not involved. Instead, phosphorylation‐independent CREB activation in nematode excitotoxic necrosis hinged on CRTC. CREB‐mediated transcription that depends on CRTC, but not on CREB phosphorylation, might lead to expression of a specific subset of neuroprotective genes. Elucidating conserved mechanisms of excitotoxicity‐specific CREB activation can help us focus on core neuroprotective programs in excitotoxicity. Cover Image for this issue: doi: .

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“…There was also a significant rise in CREB expression in the LPS per se group compared to the control ( p < 0.05). This could be due to the neuroinflammation induced by LPS, which triggered the rise in CREB expression as it is a neuroprotective transcription factor ( Feldmann et al, 2019 ). Lev and CS pre-treatment further increased the expression of the CREB gene, and this increment is significant at CS extract at a dose of 50 mg/L ( p < 0.05).…”

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“…However, this model was challenged by several studies suggesting that CREB can be activated without Ser133 phosphorylation ( Brindle et al, 1995 ; Impey et al, 1996 ; Briand et al, 2015 ). The discovery of the CRTC family of coactivators brought elements of explanation about how CREB-mediated transcription could be enhanced independently of Ser133 phosphorylation, and suggested the existence of a non-canonical, alternative way of CREB target genes activation ( Conkright et al, 2003 ; Iourgenko et al, 2003 ; Altarejos and Montminy, 2011 ; Parra-Damas et al, 2017b ; Feldmann et al, 2019 ). De facto , the N-terminal domain of CRTCs interacts with the dimerization and DNA-binding bZIP domain of CREB in a phosphorylation-independent manner.…”

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