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Non-canonical activation of CREB mediates neuroprotection in a Caenorhabditis elegans model 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: 10.1111/jnc.14494.

SUBMITTER: Feldmann KG

PROVIDER: S-EPMC6379135 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Non-canonical activation of CREB mediates neuroprotection in a Caenorhabditis elegans model of excitotoxic necrosis.

Feldmann K Genevieve KG Chowdhury Ayesha A Becker Jessica L JL McAlpin N'Gina N Ahmed Taqwa T Haider Syed S Richard Xia Jian X JX Diaz Karina K Mehta Monal G MG Mano Itzhak I

Journal of neurochemistry 20181220 4

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 pro ...[more]

PMID: 30447010

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Project description:DNA double-strand breaks (DSBs) are a particularly lethal form of DNA damage that must be repaired to restore genomic integrity. Canonical nonhomologous end joining (NHEJ), is a widely conserved pathway that detects and directly ligates the broken ends to repair the DSB. These events globally require the two proteins that form the Ku ring complex, Ku70 and Ku80, and the terminal ligase LIG4. While the NHEJ pathway in vertebrates is elaborated by more than a dozen factors of varying conservation and is similarly complex in other eukaryotes, the entire known NHEJ toolkit in Caenorhabditis elegans consists only of the core components CKU-70, CKU-80, and LIG-4 Here, we report the discovery of the first accessory NHEJ factor in C. elegans Our analysis of the DNA damage response in young larvae revealed that the canonical wild-type N2 strain consisted of two lines that exhibited a differential phenotypic response to ionizing radiation (IR). Following the mapping of the causative locus to a candidate on chromosome V and clustered regularly interspaced short palindromic repeats-Cas9 mutagenesis, we show that disruption of the nhj-1 sequence induces IR sensitivity in the N2 line that previously exhibited IR resistance. Using genetic and cytological analyses, we demonstrate that nhj-1 functions in the NHEJ pathway to repair DSBs. Double mutants of nhj-1 and lig-4 or cku-80 do not exhibit additive IR sensitivity, and the post-IR somatic and fertility phenotypes of nhj-1 mimic those of the other NHEJ factors. Furthermore, in com-1 mutants that permit repair of meiotic DSBs by NHEJ instead of restricting their repair to the homologous recombination pathway, loss of nhj-1 mimics the consequences of loss of lig-4 Diakinesis-stage nuclei in nhj-1; com-1 and nhj-1; lig-4 mutant germlines exhibit increased numbers of DAPI-staining bodies, consistent with increased chromosome fragmentation in the absence of NHEJ-mediated meiotic DSB repair. Finally, we show that NHJ-1 and LIG-4 localize to somatic nuclei in larvae, but are excluded from the germline progenitor cells, consistent with NHEJ being the dominant DNA repair pathway in the soma. nhj-1 shares no sequence homology with other known eukaryotic NHEJ factors and is taxonomically restricted to the Rhabditid family, underscoring the evolutionary plasticity of even highly conserved pathways.

Dataset Information

Non-canonical activation of CREB mediates neuroprotection in a Caenorhabditis elegans model of excitotoxic necrosis.

Publications

Non-canonical activation of CREB mediates neuroprotection in a Caenorhabditis elegans model of excitotoxic necrosis.

Similar Datasets

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