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

Vohra, Bhupinder P.S.; Groshong, Jason S.; Zayas, Roberto; Wollmann, Robert L.; Gómez, Christopher M.

doi:10.1016/j.nbd.2006.04.018

Cited by 12 publications

(15 citation statements)

References 33 publications

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“…Previous studies have shown that Ca 2+ accumulates to histochemically detectable levels at NMJs in human SCS and in εL269F SCS mice and increases within minutes after neuromuscular activity, in part due to release from internal stores (1,10,15,17). Figure 2A shows that these focal Ca 2+ accumulations are also dependent on intact muscle innervation.…”

Section: Muscle Calpain Activity Is Elevated In a Transgenic Model Ofmentioning

confidence: 76%

“…Recently, we demonstrated that activated forms of the cysteine protease caspases are present at the NMJ in muscle biopsies of SCS patients and in εL269F mice (15,16). Here we used the caspase fluorescent label sulforhodamine-labeled VAD-FMK (SR-VAD-FMK) in acutely dissociated FDB muscle fibers to compare caspase enzymatic activity in εL269F SCS and CS/εL269F mice ( Figure 9, A and B, respectively).…”

Section: Figurementioning

confidence: 99%

“…Caspases are also activated at the NMJ in SCS, and organellar degeneration resolves in close parallel to the disappearance of caspase activity after axotomy (15,16). However, activated caspases persist at the NMJ in SCS after calpain inhibition by CS (Figure 9).…”

Section: Figurementioning

confidence: 99%

“…Activation of endogenous proteolytic enzymes plays a prominent role in cell death, in muscular dystrophy, and in neurodegenerative diseases (11)(12)(13). We previously showed that some forms of the cysteine proteases, caspases that play a prominent role in the apoptotic cascade, are locally activated at the NMJ in SCS and in its transgenic mouse model (14,15). Calcium overload of muscle fibers that is highly localized to the NMJ in SCS might exhaust calcium buffering reserves and activate the calcium-activated cysteine protease calpain.…”

Section: Introductionmentioning

confidence: 99%

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Calpain activation impairs neuromuscular transmission in a mouse model of the slow-channel myasthenic syndrome

et al. 2007

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The slow-channel myasthenic syndrome (SCS) is a hereditary disorder of the acetylcholine receptor (AChR) of the neuromuscular junction (NMJ) that leads to prolonged AChR channel opening, Ca 2+ overload, and degeneration of the NMJ. We used an SCS transgenic mouse model to investigate the role of the calcium-activated protease calpain in the pathogenesis of synaptic dysfunction in SCS. Cleavage of a fluorogenic calpain substrate was increased at the NMJ of dissociated muscle fibers. Inhibition of calpain using a calpastatin (CS) transgene improved strength and neuromuscular transmission. CS caused a 2-fold increase in the frequency of miniature endplate currents (MEPCs) and an increase in NMJ size, but MEPC amplitudes remained reduced. Persistent degeneration of the NMJ was associated with localized activation of the non-calpain protease caspase-3. This study suggests that calpain may act presynaptically to impair NMJ function in SCS but further reveals a role for other cysteine proteases whose inhibition may be of additional therapeutic benefit in SCS and other excitotoxic disorders. IntroductionThe slow-channel congenital myasthenic syndrome (SCS) is a dominantly inherited neuromuscular disorder characterized by impaired neuromuscular transmission and degeneration of the neuromuscular junction (NMJ) (1-3). Patients with SCS manifest fatigability and progressive weakness of the skeletal muscles, with symptoms ranging from eye muscle and mild limb weakness to severe incapacitation and respiratory failure. Ultrastructural study of muscle in SCS reveals a focal degenerative and remodeling process selectively localized to the NMJ termed endplate myopathy. This progressive, purely synaptic disease process, in which the cleft is widened and nerve terminals are shrunken, is characterized by expansion and degeneration of postsynaptic folds as well as degeneration of subsynaptic nuclei, mitochondria, and myofibrils (1-4).The SCS is caused by missense mutations within the genes encoding nicotinic acetylcholine receptor (AChR) subunits. The mutations alter the AChR channel gating function, causing prolonged activation events, persistent synaptic currents, and localized calcium overload at the NMJ, amplified by calcium release from intracellular stores (1, 3, 5-10). These changes lead to weakness and impaired neuromuscular transmission through an effect on both pre- and postsynaptic determinants of synaptic transmission, including quantal release, synaptic cleft anatomy, and the

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Section: Muscle Calpain Activity Is Elevated In a Transgenic Model Ofmentioning

confidence: 76%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Calpain activation impairs neuromuscular transmission in a mouse model of the slow-channel myasthenic syndrome

et al. 2007

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“…25 Another study in the slow-channel mouse model showed that a signaling system mediated by the AChR, calcium, and the inositol-1,4,5-triphosphate receptor is responsible for localized calcium overload, one factor leading to myopathy in this subtype of CMS. 26 More and more detailed information during recent years about these mechanisms and about the neural agrin-Dok-7-MuSK-Rapsyn-AChR pathway can help in developing specific agents that block aberrant pathological reactions or enhance single necessary steps in these cascades. [27][28][29][30] To date, ten different types of CMS are known, and further CMS subtypes and their genetic cause may be disclosed with future investigation.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Strategies in Congenital Myasthenic Syndromes

Schara

Lochmüller

2008

Neurotherapeutics

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Summary:Congenital myasthenic syndromes (CMS) are classified in terms of the located defect: presynaptic, postsynaptic, and synaptic. They are inherited disorders caused by various genetic defects, all but the slow-channel CMS by recessive inheritance. To date, 10 different CMS are known and further CMS subtypes and their genetic cause may be disclosed by future investigations. Prognosis in CMS is variable and largely depends on the pathophysiological and genetic defect. Subtypes showing progression and life-threatening crises with apneas are generally less favorable than others. Therapeutic agents used in CMS depend on the underlying defect and include acetylcholinesterase inhibitor, 3,4-diaminopyridine, quinidine sulfate, fluoxetine, acetazolamide, and ephedrine. Although there are no double-blind, placebo-controlled clinical trials for CMS, several drugs have shown convincingly positive clinical effects. It is therefore necessary to start a rational therapy regime as early as possible. In most CMS, however, mild and severe clinical courses are reported, which makes assessment on an individual basis necessary. This review emphasizes therapeutic strategies in CMS.

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Nicotinic AChR in Congenital Myasthenic Syndromes

Grassi

Fucile

2013

Pathologies of Calcium Channels

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About 20 % of the identified cases of congenital myasthenic syndromes are due to defects causing\ud overstimulation of endplate ACh receptors, with consequent excessive Ca2+ entry, endplate structural\ud damage, and impairment of the neuromuscular transmission. Overstimulation arises from extended\ud dwelling of ACh in the synaptic cleft because of absence of acetylcholine esterase or from prolonged\ud activation of “slow-channel” mutant ACh receptors. The high Ca2+ permeability of human endplate ACh\ud receptor, recently described likely predisposes to excitotoxic damage. The good knowledge of ACh\ud receptor function has allowed molecular understanding of the defects introduced in channel kinetics and\ud Ca2+ permeability by slow-channel mutations and the design of efficient therapeutic strategies. These\ud forms of congenital myasthenic syndrome are treated by limiting ACh-induced cation entry, thus\ud preventing endplate degeneration. Several molecules of wide clinical use, such as fluoxetine and quinidine,\ud but also verapamil and salbutamol modulate AChR kinetics and ion selectivity and may be used to lower\ud ACh-evoked responses in these patients. In this contribution we summarize the main findings in the field

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

Cited by 12 publications

References 33 publications

Calpain activation impairs neuromuscular transmission in a mouse model of the slow-channel myasthenic syndrome

Calpain activation impairs neuromuscular transmission in a mouse model of the slow-channel myasthenic syndrome

Therapeutic Strategies in Congenital Myasthenic Syndromes

Nicotinic AChR in Congenital Myasthenic Syndromes

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