AIM: Neuromuscular junction (NMJ) represents the morphofunctional interface between muscle and nerve. Several chronic pathologies such as aging and neurodegenerative diseases, including muscular dystrophy and amyotrophic lateral sclerosis, display altered NMJ and functional denervation. However, the triggers and the molecular mechanisms underlying the dismantlement of NMJ remain unclear. RESULTS: Here we provide evidence that perturbation in redox signaling cascades, induced by muscle-specific accumulation of mutant SOD1G93A in transgenic MLC/SOD1G93A mice, is causally linked to morphological alterations of the neuromuscular presynaptic terminals, high turnover rate of acetylcholine receptor, and NMJ dismantlement. The analysis of potential molecular mechanisms that mediate the toxic activity of SOD1G93A revealed a causal link between protein kinase Cθ (PKCθ) activation and NMJ disintegration. INNOVATION: The study discloses the molecular mechanism that triggers functional denervation associated with the toxic activity of muscle SOD1G93A expression and suggests the possibility of developing a new strategy to counteract age- and pathology-associated denervation based on pharmacological inhibition of PKCθ activity. CONCLUSIONS: Collectively, these data indicate that muscle-specific accumulation of oxidative damage can affect neuromuscular communication and induce NMJ dismantlement through a PKCθ-dependent mechanism.

Muscle expression of SOD1(G93A) triggers the dismantlement of neuromuscular junction via PKC-theta / Dobrowolny, Gabriella; Martini, Martina; Scicchitano, Bianca Maria; Romanello, Vanina; Boncompagni, Simona; Nicoletti, Carmine; Pietrangelo, Laura; De Panfilis, Simone; Catizone, Angiolina; Bouchè, Marina; Sandri, Marco; Rudolf, Rüdiger; Protasi, Feliciano; Musarò, Antonio. - In: ANTIOXIDANTS & REDOX SIGNALING. - ISSN 1523-0864. - ELETTRONICO. - 28:12(2018), pp. 1105-1119. [10.1089/ars.2017.7054]

Muscle expression of SOD1(G93A) triggers the dismantlement of neuromuscular junction via PKC-theta

Dobrowolny, Gabriella;Martini, Martina;Nicoletti, Carmine;De Panfilis, Simone;Catizone, Angiolina;Bouchè, Marina;Musarò, Antonio
2018

Abstract

AIM: Neuromuscular junction (NMJ) represents the morphofunctional interface between muscle and nerve. Several chronic pathologies such as aging and neurodegenerative diseases, including muscular dystrophy and amyotrophic lateral sclerosis, display altered NMJ and functional denervation. However, the triggers and the molecular mechanisms underlying the dismantlement of NMJ remain unclear. RESULTS: Here we provide evidence that perturbation in redox signaling cascades, induced by muscle-specific accumulation of mutant SOD1G93A in transgenic MLC/SOD1G93A mice, is causally linked to morphological alterations of the neuromuscular presynaptic terminals, high turnover rate of acetylcholine receptor, and NMJ dismantlement. The analysis of potential molecular mechanisms that mediate the toxic activity of SOD1G93A revealed a causal link between protein kinase Cθ (PKCθ) activation and NMJ disintegration. INNOVATION: The study discloses the molecular mechanism that triggers functional denervation associated with the toxic activity of muscle SOD1G93A expression and suggests the possibility of developing a new strategy to counteract age- and pathology-associated denervation based on pharmacological inhibition of PKCθ activity. CONCLUSIONS: Collectively, these data indicate that muscle-specific accumulation of oxidative damage can affect neuromuscular communication and induce NMJ dismantlement through a PKCθ-dependent mechanism.
2018
ALS; NMJ; PKC; aging; mitochondrial defects; oxidative damage
01 Pubblicazione su rivista::01a Articolo in rivista
Muscle expression of SOD1(G93A) triggers the dismantlement of neuromuscular junction via PKC-theta / Dobrowolny, Gabriella; Martini, Martina; Scicchitano, Bianca Maria; Romanello, Vanina; Boncompagni, Simona; Nicoletti, Carmine; Pietrangelo, Laura; De Panfilis, Simone; Catizone, Angiolina; Bouchè, Marina; Sandri, Marco; Rudolf, Rüdiger; Protasi, Feliciano; Musarò, Antonio. - In: ANTIOXIDANTS & REDOX SIGNALING. - ISSN 1523-0864. - ELETTRONICO. - 28:12(2018), pp. 1105-1119. [10.1089/ars.2017.7054]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1014989
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