Calpain-Mediated Degradation of Drebrin by Excitotoxicity In vitro and In vivo

The level of drebrin, an evolutionarily conserved f-actin-binding protein that regulates synaptic structure and function, is reduced in the brains of patients with chronic neurodegenerative diseases such as Alzheimer’s disease (AD) and Down’s syndrome (DS). It was suggested that excitotoxic neuronal...

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Main Authors:	Chimura, Takahiko, Launey, Thomas, Yoshida, Nobuaki
Format:	Online
Language:	English
Published:	Public Library of Science 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408054/

id	pubmed-4408054
recordtype	oai_dc
spelling	pubmed-44080542015-05-04 Calpain-Mediated Degradation of Drebrin by Excitotoxicity In vitro and In vivo Chimura, Takahiko Launey, Thomas Yoshida, Nobuaki Research Article The level of drebrin, an evolutionarily conserved f-actin-binding protein that regulates synaptic structure and function, is reduced in the brains of patients with chronic neurodegenerative diseases such as Alzheimer’s disease (AD) and Down’s syndrome (DS). It was suggested that excitotoxic neuronal death caused by overactivation of NMDA-type glutamate receptors (NMDARs) occurs in AD and DS; however, the relationship between excitotoxicity and drebrin loss is unknown. Here, we show that drebrin is a novel target of calpain-mediated proteolysis under excitotoxic conditions induced by the overactivation of NMDARs. In cultured rodent neurons, degradation of drebrin was confirmed by the detection of proteolytic fragments, as well as a reduction in the amount of full-length drebrin. Notably, the NMDA-induced degradation of drebrin in mature neurons occurred concomitantly with a loss of f-actin. Furthermore, pharmacological inhibition of f-actin loss facilitated the drebrin degradation, suggesting a functional linkage between f-actin and drebrin degradation. Biochemical analyses using purified drebrin and calpain revealed that calpain degraded drebrin directly in vitro. Furthermore, cerebral ischemia also induced the degradation of drebrin in vivo. These findings suggest that calpain-mediated degradation of drebrin is a fundamental pathology of neurodegenerative diseases mediated by excitotoxicity, regardless of whether they are acute or chronic. Drebrin regulates the synaptic clustering of NMDARs; therefore, degradation of drebrin under excitotoxic conditions may modulate NMDAR-mediated signal transductions, including pro-survival signaling. Overall, the results presented here provide novel insights into the molecular basis of cellular responses to excitotoxicity in vitro and in vivo. Public Library of Science 2015-04-23 /pmc/articles/PMC4408054/ /pubmed/25905636 http://dx.doi.org/10.1371/journal.pone.0125119 Text en © 2015 Chimura et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Chimura, Takahiko Launey, Thomas Yoshida, Nobuaki
spellingShingle	Chimura, Takahiko Launey, Thomas Yoshida, Nobuaki Calpain-Mediated Degradation of Drebrin by Excitotoxicity In vitro and In vivo
author_facet	Chimura, Takahiko Launey, Thomas Yoshida, Nobuaki
author_sort	Chimura, Takahiko
title	Calpain-Mediated Degradation of Drebrin by Excitotoxicity In vitro and In vivo
title_short	Calpain-Mediated Degradation of Drebrin by Excitotoxicity In vitro and In vivo
title_full	Calpain-Mediated Degradation of Drebrin by Excitotoxicity In vitro and In vivo
title_fullStr	Calpain-Mediated Degradation of Drebrin by Excitotoxicity In vitro and In vivo
title_full_unstemmed	Calpain-Mediated Degradation of Drebrin by Excitotoxicity In vitro and In vivo
title_sort	calpain-mediated degradation of drebrin by excitotoxicity in vitro and in vivo
description	The level of drebrin, an evolutionarily conserved f-actin-binding protein that regulates synaptic structure and function, is reduced in the brains of patients with chronic neurodegenerative diseases such as Alzheimer’s disease (AD) and Down’s syndrome (DS). It was suggested that excitotoxic neuronal death caused by overactivation of NMDA-type glutamate receptors (NMDARs) occurs in AD and DS; however, the relationship between excitotoxicity and drebrin loss is unknown. Here, we show that drebrin is a novel target of calpain-mediated proteolysis under excitotoxic conditions induced by the overactivation of NMDARs. In cultured rodent neurons, degradation of drebrin was confirmed by the detection of proteolytic fragments, as well as a reduction in the amount of full-length drebrin. Notably, the NMDA-induced degradation of drebrin in mature neurons occurred concomitantly with a loss of f-actin. Furthermore, pharmacological inhibition of f-actin loss facilitated the drebrin degradation, suggesting a functional linkage between f-actin and drebrin degradation. Biochemical analyses using purified drebrin and calpain revealed that calpain degraded drebrin directly in vitro. Furthermore, cerebral ischemia also induced the degradation of drebrin in vivo. These findings suggest that calpain-mediated degradation of drebrin is a fundamental pathology of neurodegenerative diseases mediated by excitotoxicity, regardless of whether they are acute or chronic. Drebrin regulates the synaptic clustering of NMDARs; therefore, degradation of drebrin under excitotoxic conditions may modulate NMDAR-mediated signal transductions, including pro-survival signaling. Overall, the results presented here provide novel insights into the molecular basis of cellular responses to excitotoxicity in vitro and in vivo.
publisher	Public Library of Science
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408054/
_version_	1613215103269732352

Calpain-Mediated Degradation of Drebrin by Excitotoxicity In vitro and In vivo

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