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

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...

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Autores principales: Ameen, S. Sadia, Griem-Krey, Nane, Dufour, Antoine, Hossain, M. Iqbal, Hoque, Ashfaqul, Sturgeon, Sharelle, Nandurkar, Harshal, Draxler, Dominik F., Medcalf, Robert L., Kamaruddin, Mohd Aizuddin, Lucet, Isabelle S., Leeming, Michael G., Liu, Dazhi, Dhillon, Amardeep, Lim, Jet Phey, Basheer, Faiza, Zhu, Hong-Jian, Bokhari, Laita, Roulston, Carli L., Paradkar, Prasad N., Kleifeld, Oded, Clarkson, Andrew N., Wellendorph, Petrine, Ciccotosto, Giuseppe D., Williamson, Nicholas A., Ang, Ching-Seng, Cheng, Heung-Chin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10199228/
https://www.ncbi.nlm.nih.gov/pubmed/37030595
http://dx.doi.org/10.1016/j.mcpro.2023.100543
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author Ameen, S. Sadia
Griem-Krey, Nane
Dufour, Antoine
Hossain, M. Iqbal
Hoque, Ashfaqul
Sturgeon, Sharelle
Nandurkar, Harshal
Draxler, Dominik F.
Medcalf, Robert L.
Kamaruddin, Mohd Aizuddin
Lucet, Isabelle S.
Leeming, Michael G.
Liu, Dazhi
Dhillon, Amardeep
Lim, Jet Phey
Basheer, Faiza
Zhu, Hong-Jian
Bokhari, Laita
Roulston, Carli L.
Paradkar, Prasad N.
Kleifeld, Oded
Clarkson, Andrew N.
Wellendorph, Petrine
Ciccotosto, Giuseppe D.
Williamson, Nicholas A.
Ang, Ching-Seng
Cheng, Heung-Chin
author_facet Ameen, S. Sadia
Griem-Krey, Nane
Dufour, Antoine
Hossain, M. Iqbal
Hoque, Ashfaqul
Sturgeon, Sharelle
Nandurkar, Harshal
Draxler, Dominik F.
Medcalf, Robert L.
Kamaruddin, Mohd Aizuddin
Lucet, Isabelle S.
Leeming, Michael G.
Liu, Dazhi
Dhillon, Amardeep
Lim, Jet Phey
Basheer, Faiza
Zhu, Hong-Jian
Bokhari, Laita
Roulston, Carli L.
Paradkar, Prasad N.
Kleifeld, Oded
Clarkson, Andrew N.
Wellendorph, Petrine
Ciccotosto, Giuseppe D.
Williamson, Nicholas A.
Ang, Ching-Seng
Cheng, Heung-Chin
author_sort Ameen, S. Sadia
collection PubMed
description 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.
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spelling pubmed-101992282023-05-21 N-Terminomic Changes in Neurons During Excitotoxicity Reveal Proteolytic Events Associated With Synaptic Dysfunctions and Potential Targets for Neuroprotection Ameen, S. Sadia Griem-Krey, Nane Dufour, Antoine Hossain, M. Iqbal Hoque, Ashfaqul Sturgeon, Sharelle Nandurkar, Harshal Draxler, Dominik F. Medcalf, Robert L. Kamaruddin, Mohd Aizuddin Lucet, Isabelle S. Leeming, Michael G. Liu, Dazhi Dhillon, Amardeep Lim, Jet Phey Basheer, Faiza Zhu, Hong-Jian Bokhari, Laita Roulston, Carli L. Paradkar, Prasad N. Kleifeld, Oded Clarkson, Andrew N. Wellendorph, Petrine Ciccotosto, Giuseppe D. Williamson, Nicholas A. Ang, Ching-Seng Cheng, Heung-Chin Mol Cell Proteomics Research 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. American Society for Biochemistry and Molecular Biology 2023-04-06 /pmc/articles/PMC10199228/ /pubmed/37030595 http://dx.doi.org/10.1016/j.mcpro.2023.100543 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research
Ameen, S. Sadia
Griem-Krey, Nane
Dufour, Antoine
Hossain, M. Iqbal
Hoque, Ashfaqul
Sturgeon, Sharelle
Nandurkar, Harshal
Draxler, Dominik F.
Medcalf, Robert L.
Kamaruddin, Mohd Aizuddin
Lucet, Isabelle S.
Leeming, Michael G.
Liu, Dazhi
Dhillon, Amardeep
Lim, Jet Phey
Basheer, Faiza
Zhu, Hong-Jian
Bokhari, Laita
Roulston, Carli L.
Paradkar, Prasad N.
Kleifeld, Oded
Clarkson, Andrew N.
Wellendorph, Petrine
Ciccotosto, Giuseppe D.
Williamson, Nicholas A.
Ang, Ching-Seng
Cheng, Heung-Chin
N-Terminomic Changes in Neurons During Excitotoxicity Reveal Proteolytic Events Associated With Synaptic Dysfunctions and Potential Targets for Neuroprotection
title N-Terminomic Changes in Neurons During Excitotoxicity Reveal Proteolytic Events Associated With Synaptic Dysfunctions and Potential Targets for Neuroprotection
title_full N-Terminomic Changes in Neurons During Excitotoxicity Reveal Proteolytic Events Associated With Synaptic Dysfunctions and Potential Targets for Neuroprotection
title_fullStr N-Terminomic Changes in Neurons During Excitotoxicity Reveal Proteolytic Events Associated With Synaptic Dysfunctions and Potential Targets for Neuroprotection
title_full_unstemmed N-Terminomic Changes in Neurons During Excitotoxicity Reveal Proteolytic Events Associated With Synaptic Dysfunctions and Potential Targets for Neuroprotection
title_short N-Terminomic Changes in Neurons During Excitotoxicity Reveal Proteolytic Events Associated With Synaptic Dysfunctions and Potential Targets for Neuroprotection
title_sort n-terminomic changes in neurons during excitotoxicity reveal proteolytic events associated with synaptic dysfunctions and potential targets for neuroprotection
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10199228/
https://www.ncbi.nlm.nih.gov/pubmed/37030595
http://dx.doi.org/10.1016/j.mcpro.2023.100543
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