Autism-associated SHANK3 mutations impair maturation of neuromuscular junctions and striated muscles

Anne-Kathrin Lutz; Stefanie Pfaender; Berra Incearap; Valentin Ioannidis; Ilaria Ottonelli; Karl J. Föhr; Judith Cammerer; Marvin Zoller; Julia Higelin; Federica Giona; Maximilian Stetter; Nicole Stoecker; Najwa Ouali Alami; Michael P. Schön; Michael Orth; Stefan Liebau; Gotthold Barbi; Andreas M. Grabrucker; Richard Delorme; Michael Fauler; Benjamin Mayer; Sarah Jesse; Francesco Roselli; Albert C. Ludolph; Thomas Bourgeron; Chiara Verpelli; Maria Demestre; Tobias M. Boeckers

doi:10.1126/scitranslmed.aaz3267

Key Points

To investigate the role of autism-associated SHANK3 mutations in neuromuscular junction and striated muscle maturation, and assess potential rescue strategies.
Evaluated neuromuscular junction maturation and striated muscle development in mouse models harboring autism-associated SHANK3 mutations.
Administered the fast skeletal troponin activator Tirasemtiv to test the rescue of muscle fiber calcium sensitivity and maturation defects.
Mutations in SHANK3 caused distinct impairment in the maturation of both neuromuscular junctions and striated muscles outside the central nervous system.
Treatment with the troponin activator Tirasemtiv sensitized muscle fibers to calcium and successfully rescued the neuromuscular and muscular deficits in mutant mice.

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Implication

Animal study demonstrates that SHANK3 mutations impair muscle and neuromuscular maturation in mice, indicating therapeutic potential for troponin activators in autism.

Abstract

mice could be rescued with the troponin activator Tirasemtiv that sensitizes muscle fibers to calcium. Our observations give insight into the function of SHANK3 besides the central nervous system and imply potential treatment strategies for SHANK3-associated ASD.

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Cite This Study

Lutz et al. (2020) studied this question.

synapsesocial.com/papers/6a195e6d001a20a9c0d95c11 https://doi.org/10.1126/scitranslmed.aaz3267

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Autism-associated SHANK3 mutations impair maturation of neuromuscular junctions and striated muscles

Key Points

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Cite This Study

Autism-associated SHANK3 mutations impair maturation of neuromuscular junctions and striated muscles

Key Points

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Implication

Abstract

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Cite This Study

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