Activation of apoptotic pathways at muscle fiber synapses is circumscribed and reversible in a slow-channel syndrome model

In the slow-channel syndrome (SCS) mutant acetylcholine receptors elicit calcium overload and myonuclear degeneration at the neuromuscular junction (NMJ), without muscle fiber death. Activated caspases are present at SCS motor endplates. We hypothesized that SCS represents a limited form of apoptosi...

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Main Authors:	Bhupinder P.S. Vohra, Jason S. Groshong, Roberto Zayas, Robert L. Wollmann, Christopher M. Gomez
Format:	Article
Language:	English
Published:	Elsevier 2006-08-01
Series:	Neurobiology of Disease
Subjects:	Caspase Apoptosis Channelopathy Mutation Acetylcholine receptor Neuromuscular junction
Online Access:	http://www.sciencedirect.com/science/article/pii/S0969996106000830

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record_format	Article
spelling	doaj-15d370629a8b4762bd00c087599455cd2021-03-20T04:52:52ZengElsevierNeurobiology of Disease1095-953X2006-08-01232462470Activation of apoptotic pathways at muscle fiber synapses is circumscribed and reversible in a slow-channel syndrome modelBhupinder P.S. Vohra0Jason S. Groshong1Roberto Zayas2Robert L. Wollmann3Christopher M. Gomez4Washington University School of Medicine, Department of Pediatrics, St. Louis, MO 63110, USAUniversity of Minnesota, Department of Neurology, MMC295, 420 Delaware Street SE, Minneapolis, MN 55455, USAUniversity of Minnesota, Department of Neurology, MMC295, 420 Delaware Street SE, Minneapolis, MN 55455, USAUniversity of Chicago Hospitals, Department of Pathology, BSD, AMB S237, MC2030, 5841 S. Maryland, Chicago, IL 60637, USADepartment of Neurology, BSD, AMB S237, MC2030, 5841 S. Maryland, Chicago, IL 60637, USA; Corresponding author. Fax: +1 773 702 5670.In the slow-channel syndrome (SCS) mutant acetylcholine receptors elicit calcium overload and myonuclear degeneration at the neuromuscular junction (NMJ), without muscle fiber death. Activated caspases are present at SCS motor endplates. We hypothesized that SCS represents a limited form of apoptosis. We found condensed chromatin and occasional single-strand DNA nicks in degenerating synaptic nuclei. Cleaved forms of caspases-3 and -9 were present in mouse SCS muscle homogenates and were specifically localized to NMJs. Finally, interruption of cholinergic activity by axotomy markedly reduced NMJ caspase activity and improved the morphological features of apoptosis at NMJs. These results demonstrate that in SCS processes leading to apoptosis may remain compartmentalized and reversible. Use of cysteine protease inhibitors may aid in treatment of this and other dystrophic muscle and excitotoxic disorders. Identification of extrasynaptic factors that prevent the spread of apoptosis in SCS muscle fibers may aid in developing treatments for neurological disorders characterized by excitotoxicity or apoptosis.http://www.sciencedirect.com/science/article/pii/S0969996106000830CaspaseApoptosisChannelopathyMutationAcetylcholine receptorNeuromuscular junction
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Bhupinder P.S. Vohra Jason S. Groshong Roberto Zayas Robert L. Wollmann Christopher M. Gomez
spellingShingle	Bhupinder P.S. Vohra Jason S. Groshong Roberto Zayas Robert L. Wollmann Christopher M. Gomez Activation of apoptotic pathways at muscle fiber synapses is circumscribed and reversible in a slow-channel syndrome model Neurobiology of Disease Caspase Apoptosis Channelopathy Mutation Acetylcholine receptor Neuromuscular junction
author_facet	Bhupinder P.S. Vohra Jason S. Groshong Roberto Zayas Robert L. Wollmann Christopher M. Gomez
author_sort	Bhupinder P.S. Vohra
title	Activation of apoptotic pathways at muscle fiber synapses is circumscribed and reversible in a slow-channel syndrome model
title_short	Activation of apoptotic pathways at muscle fiber synapses is circumscribed and reversible in a slow-channel syndrome model
title_full	Activation of apoptotic pathways at muscle fiber synapses is circumscribed and reversible in a slow-channel syndrome model
title_fullStr	Activation of apoptotic pathways at muscle fiber synapses is circumscribed and reversible in a slow-channel syndrome model
title_full_unstemmed	Activation of apoptotic pathways at muscle fiber synapses is circumscribed and reversible in a slow-channel syndrome model
title_sort	activation of apoptotic pathways at muscle fiber synapses is circumscribed and reversible in a slow-channel syndrome model
publisher	Elsevier
series	Neurobiology of Disease
issn	1095-953X
publishDate	2006-08-01
description	In the slow-channel syndrome (SCS) mutant acetylcholine receptors elicit calcium overload and myonuclear degeneration at the neuromuscular junction (NMJ), without muscle fiber death. Activated caspases are present at SCS motor endplates. We hypothesized that SCS represents a limited form of apoptosis. We found condensed chromatin and occasional single-strand DNA nicks in degenerating synaptic nuclei. Cleaved forms of caspases-3 and -9 were present in mouse SCS muscle homogenates and were specifically localized to NMJs. Finally, interruption of cholinergic activity by axotomy markedly reduced NMJ caspase activity and improved the morphological features of apoptosis at NMJs. These results demonstrate that in SCS processes leading to apoptosis may remain compartmentalized and reversible. Use of cysteine protease inhibitors may aid in treatment of this and other dystrophic muscle and excitotoxic disorders. Identification of extrasynaptic factors that prevent the spread of apoptosis in SCS muscle fibers may aid in developing treatments for neurological disorders characterized by excitotoxicity or apoptosis.
topic	Caspase Apoptosis Channelopathy Mutation Acetylcholine receptor Neuromuscular junction
url	http://www.sciencedirect.com/science/article/pii/S0969996106000830
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Activation of apoptotic pathways at muscle fiber synapses is circumscribed and reversible in a slow-channel syndrome model

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