Focal Caspase Activation Underlies the Endplate Myopathy in Slow-Channel Syndrome

Bhupinder P S Vohra, Jason S. Groshong, Ricardo A Maselli, M. Anthony Verity, Robert L. Wollmann, Christopher M. Gomez

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26 Scopus citations

Abstract

Slow-channel syndrome (SCS) is a progressive neuromuscular disorder caused by abnormal gating of mutant acetylcholine receptors (AChRs) in the neuromuscular junction (NMJ). The pathological hallmark is selective degeneration of the NMJ termed endplate myopathy. Endplate myopathy consists of a combination of ultrastructural abnormalities, including degenerating subsynaptic nuclei, mitochondria, and postsynaptic folds, caused by localized cation overload through mutant AChRs. Because some of these changes resemble those seen in programmed cell death, we evaluated SCS muscle for evidence of focal activation of apoptotic pathways. Using antisera specific for the activated forms of caspases, the family of cysteine proteases that underlies apoptosis, we demonstrated that active forms of initiator and effector caspases are selectively localized at the NMJ in SCS. In comparison with an electron microscopic assessment of the abnormalities seen in endplate myopathy, we found that activated caspases were present at between 15 and 57% of endplates, similar to the proportion of endplates with degenerating mitochondria or vacuoles. This greatly exceeds the number of NMJs exhibiting nuclear degeneration. These findings provide the first evidence supporting the view that caspase activation in human disease can play a prominent role in localized cellular degenerative processes without causing nuclear or cell death.

Original languageEnglish (US)
Pages (from-to)347-352
Number of pages6
JournalAnnals of Neurology
Volume55
Issue number3
DOIs
StatePublished - Mar 2004

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ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Vohra, B. P. S., Groshong, J. S., Maselli, R. A., Verity, M. A., Wollmann, R. L., & Gomez, C. M. (2004). Focal Caspase Activation Underlies the Endplate Myopathy in Slow-Channel Syndrome. Annals of Neurology, 55(3), 347-352. https://doi.org/10.1002/ana.10823