Ccp1, a tubulin deglutamylase, increases survival of rodent spinal cord neurons following glutamate-induced excitotoxicity

Yasmin H. Ramadan, Amanda Gu, Nicole Ross, Sara A. McEwan, Maureen M. Barr, Bonnie L. Firestein, Robert O’hagan

Research output: Contribution to journalArticlepeer-review

Abstract

Microtubules (MTs) are cytoskeletal elements that provide structural support and act as roadways for intracellular transport in cells. MTs are also needed for neurons to extend and maintain long axons and dendrites that establish connectivity to transmit information through the nervous system. Therefore, in neurons, the ability to independently regulate cytoskeletal stability and MT-based transport in different cellular compartments is essential. Posttranslational modification of MTs is one mechanism by which neurons regulate the cytoskeleton. The carboxypeptidase CCP1 negatively regulates posttranslational polyglutamylation of MTs. In mammals, loss of CCP1, and the resulting hyper-glutamylation of MTs, causes neurodegeneration. It has also long been known that CCP1 expression is activated by neuronal injury; however, whether CCP1 plays a neuroprotective role after injury is unknown. Using shRNA-mediated knock-down of CCP1 in embryonic rat spinal cord cultures, we demonstrate that CCP1 protects spinal cord neurons from excitotoxic death. Unexpectedly, excitotoxic injury reduced CCP1 expression in our system. We previously demonstrated that the CCP1 homolog in Caenorhabditis elegans is important for maintenance of neuronal cilia. Although cilia enhance neuronal survival in some contexts, it is not yet clear whether CCP1 maintains cilia in mam-malian spinal cord neurons. We found that knock-down of CCP1 did not result in loss or shortening of cilia in cul-tured spinal cord neurons, suggesting that its effect on survival of excitotoxicity is independent of cilia. Our results support the idea that enzyme regulators of MT polyglutamylation might be therapeutically targeted to prevent excito-toxic death after spinal cord injuries.

Original languageEnglish (US)
Article numberENEURO.0431-20.2021
JournaleNeuro
Volume8
Issue number2
DOIs
StatePublished - 2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Keywords

  • Cilia
  • Excitotoxicity
  • Neuronal injury
  • Neuroprotection
  • Polyglutamylation
  • Spinal cord

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