N-Terminomic Changes of Neurons During Excitotoxicity Reveal Proteolytic Events Associated with Synaptic Dysfunctions and Potential Targets for Neuroprotection

Ameen, SS; Griem-Krey, N; Dufour, A; Hossain, MI; Hoque, A; Sturgeon, S; Nandurkar, H; Draxler, DF; Medcalf, RL; Kamaruddin, MA; Lucet, IS; Leeming, MG; Liu, D; Dhillon, A; Lim, JP; Basheer, F; Zhu, HJ; Bokhari, L; Roulston, C; Paradkar, PN; Kleifeld, O; Clarkson, AN; Wellendorph, P; Ciccotosto, GD; Williamson, NA; Ang, CS; Cheng, HC

Author(s): Ameen, SS; Griem-Krey, N; Dufour, A; Hossain, MI; Hoque, A; Sturgeon, S; Nandurkar, H; Draxler, DF; Medcalf, RL; Kamaruddin, MA; Lucet, IS; Leeming, MG; Liu, D; Dhillon, A; Lim, JP; Basheer, F; Zhu, HJ; Bokhari, L; Roulston, C; Paradkar, PN; Kleifeld, O; Clarkson, AN; Wellendorph, P; Ciccotosto, GD; Williamson, NA; Ang, CS; Cheng, HC;
Details: Publication Year 2023-04-06,Volume 22,Issue #5,Page 100543
Journal Title: Molecular & Cellular Proteomics
Abstract: Excitotoxicity, a neuronal death process in neurological disorders such as stroke, is initiated by over-stimulation of ionotropic glutamate receptors. Although dysregulation of proteolytic signaling networks is critical for excitotoxicity, the identity of affected proteins and mechanisms by which they induce neuronal cell death remain unclear. To address this, we used quantitative N-terminomics to identify proteins modified by proteolysis in neurons undergoing excitotoxic cell death. We found that most proteolytically processed proteins in excitotoxic neurons are likely substrates of calpains, including key synaptic regulatory proteins such as CRMP2, doublecortin-like kinase I, Src tyrosine kinase and calmodulin-dependent protein kinase IIβ (CaMKIIβ). Critically, calpain-catalyzed proteolytic processing of these proteins generates stable truncated fragments with altered activities that potentially contribute to neuronal death by perturbing synaptic organization and function. Blocking calpain-mediated proteolysis of one of these proteins, Src, protected against neuronal loss in a rat model of neurotoxicity. Extrapolation of our N-terminomic results led to the discovery that CaMKIIα, an isoform of CaMKIIβ, undergoes differential processing in mouse brains under physiological conditions and during ischemic stroke. In summary, by identifying the neuronal proteins undergoing proteolysis during excitotoxicity, our findings offer new insights into excitotoxic neuronal death mechanisms and reveal potential neuroprotective targets for neurological disorders.
Publisher: Elsevier
Keywords: Mice; Rats; Animals; Proteolysis; *Neuroprotection; Calpain/metabolism; *Nervous System Diseases/metabolism; Neurons/metabolism; Glutamic Acid/metabolism; Cells, Cultured; Crmp2; CaM kinase IIa; CaM kinase IIb; Src; calpains; excitotoxicity; neuronal death; neuroprotection; proteolytic processing; synaptic damage
Research Division(s): Chemical Biology
PubMed ID: 37030595
Publisher's Version: https://doi.org/10.1016/j.mcpro.2023.100543
Open Access at Publisher's Site: https://doi.org/10.1016/j.mcpro.2023.100543
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-04-17 03:34:05

Last Modified: 2023-06-13 01:17:45