Back to Search
Start Over
N-Terminomic Changes in Neurons During Excitotoxicity Reveal Proteolytic Events Associated With Synaptic Dysfunctions and Potential Targets for Neuroprotection
- Source :
- Ameen, S S, Griem-Krey, N, Dufour, A, Hossain, M I, Hoque, A, Sturgeon, S, Nandurkar, H, Draxler, D F, Medcalf, R L, Kamaruddin, M A, Lucet, I S, Leeming, M G, Liu, D, Dhillon, A, Lim, J P, Basheer, F, Zhu, H J, Bokhari, L, Roulston, C L, Paradkar, P N, Kleifeld, O, Clarkson, A N, Wellendorph, P, Ciccotosto, G D, Williamson, N A, Ang, C S & Cheng, H C 2023, ' N-Terminomic Changes in Neurons During Excitotoxicity Reveal Proteolytic Events Associated With Synaptic Dysfunctions and Potential Targets for Neuroprotection ', Molecular & cellular proteomics : MCP, vol. 22, no. 5, 100543 . https://doi.org/10.1016/j.mcpro.2023.100543, Molecular & cellular proteomics : MCP, vol 22, iss 5
- Publication Year :
- 2023
-
Abstract
- Excitotoxicity, a neuronal death process in neurological disorders such as stroke, is initiated by the overstimulation 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.
- Subjects :
- Biochemistry & Molecular Biology
Cells
1.1 Normal biological development and functioning
Glutamic Acid
Biochemistry
Analytical Chemistry
Mice
Underpinning research
Genetics
Animals
2.1 Biological and endogenous factors
CaM kinase IIa
CaM kinase IIb
Aetiology
Molecular Biology
Neurons
Cultured
Calpain
Neurosciences
neuronal death
synaptic damage
Rats
Brain Disorders
Stroke
CRMP2
proteolytic processing
Proteolysis
Neurological
neuroprotection
Nervous System Diseases
calpains
excitotoxicity
Src
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Ameen, S S, Griem-Krey, N, Dufour, A, Hossain, M I, Hoque, A, Sturgeon, S, Nandurkar, H, Draxler, D F, Medcalf, R L, Kamaruddin, M A, Lucet, I S, Leeming, M G, Liu, D, Dhillon, A, Lim, J P, Basheer, F, Zhu, H J, Bokhari, L, Roulston, C L, Paradkar, P N, Kleifeld, O, Clarkson, A N, Wellendorph, P, Ciccotosto, G D, Williamson, N A, Ang, C S & Cheng, H C 2023, ' N-Terminomic Changes in Neurons During Excitotoxicity Reveal Proteolytic Events Associated With Synaptic Dysfunctions and Potential Targets for Neuroprotection ', Molecular & cellular proteomics : MCP, vol. 22, no. 5, 100543 . https://doi.org/10.1016/j.mcpro.2023.100543, Molecular & cellular proteomics : MCP, vol 22, iss 5
- Accession number :
- edsair.doi.dedup.....39a980e6e528169653b1b0ed50175569