Non-Canonical Activation of CREB Mediates Neuroprotection in a C. elegans Model of Excitotoxic Necrosis

Feldmann, K. G.; Chowdhury, A.; Becker, J.; McAlpin, N.; Ahmed, T.; Haider, S.; Xia, J. X. R.; Diaz, K.; Mehta, M. G.; Mano, I.

doi:10.1101/261420

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bioRxiv · 10.1101/261420

Non-Canonical Activation of CREB Mediates Neuroprotection in a C. elegans Model of Excitotoxic Necrosis

Feldmann, K. G.·Chowdhury, A.·Becker, J.·McAlpin, N.·Ahmed, T.·Haider, S.·Xia, J. X. R.·Diaz, K.·Mehta, M. G.·Mano, I.

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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 (CBP). However, given CREBs 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 use a C. elegans model of neurodegeneration by excitotoxic necrosis. We demonstrate that CREBs neuroprotective effect is conserved, and seems most effective in neurons with moderate Glu exposure. We find that factors mediating canonical CREB activation are not involved. Instead, phosphorylation-independent CREB activation in nematode excitotoxic necrosis hinges 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.

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Feldmann, K. G., Chowdhury, A., Becker, J., McAlpin, N., Ahmed, T., Haider, S., Xia, J. X. R., Diaz, K., Mehta, M. G., Mano, I.. 2018-02-07. Non-Canonical Activation of CREB Mediates Neuroprotection in a C. elegans Model of Excitotoxic Necrosis. https://doi.org/10.1101/261420

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