Non-canonical Activation of CREB/crh-1 Mediates Neuroprotection in a <i>Caenorhabditis elegans</i> Model of Excitotoxic Necrosis

<p>Excitotoxicity, which is a major cause of neurodegeneration in brain ischemia, can also activate neuroprotective pathways. A frequently suggested neuroprotective cascade involves the activation of the transcription factor CREB by its phosphorylation, but on its own this mode of CREB activation is promiscuous. We aim to elucidate the specific mechanism of CREB activation in excitotoxicity-induced neuroprotection, focusing on three suggested models: CREB phosphorylation by calcium-activated kinases in the cytoplasm or nucleus, and the activation of CREB by CRTC (an important cofactor). Using a <em>C. elegans</em> model of excitotoxicity, we demonstrate that CREB’s neuroprotective effect is mainly seen in neurons exposed to a moderate insult. Surprisingly, we find that CREB’s effect does not depend on the classic phosphorylation-activator CaMKK or the phosphorylation-dependent cofactor CBP. Instead, we find that the neuroprotective function of CREB in excitotoxicity depends on its cofactor CRTC/<em>crtc-1</em> and its upstream regulators. Discovering the exact mechanism of CREB activation that is important for excitotoxic neuroprotection and examining CREB-mediated regulation of conserved neuroprotective genes may allow us to find candidate targets for future therapeutic interventions in brain ischemia.</p>

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Biology

Grantor

The Graduate School and University Center of The City University of New York

Year dc:date.available

2018

Author dc:creator

• Feldmann, K. Genevieve

Advisor dc:contributor.advisor

• Itzhak Mano

Committee members dc:contributor.committeemember

• Jonathan Levitt
• Andreas Kottmann
• Monica Driscoll
• Shai Shaham
• Chris Li

• Molecular and Cellular Neuroscience
• Neuroscience and Neurobiology
• Neuroscience
• Excitotoxicity
• Neuroprotection
• CREB

Repository record dc:identifier

https://academicworks.cuny.edu/gc_etds/2590

OAI identifier oai:identifier

oai:academicworks.cuny.edu:gc_etds-3804