Date of Degree

5-2018

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Itzhak Mano

Committee Members

Jonathan Levitt

Andreas Kottmann

Monica Driscoll

Shai Shaham

Chris Li

Subject Categories

Molecular and Cellular Neuroscience | Neuroscience and Neurobiology

Keywords

Neuroscience, Excitotoxicity, Neuroprotection, CREB

Abstract

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 C. elegans 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/crtc-1 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.

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