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Collagen VI is required for the structural and functional integrity of the neuromuscular junction

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Abstract

The synaptic cleft of the neuromuscular junction (NMJ) consists of a highly specialized extracellular matrix (ECM) involved in synapse maturation, in the juxtaposition of pre- to post-synaptic areas, and in ensuring proper synaptic transmission. Key components of synaptic ECM, such as collagen IV, perlecan and biglycan, are binding partners of one of the most abundant ECM protein of skeletal muscle, collagen VI (ColVI), previously never linked to NMJ. Here, we demonstrate that ColVI is itself a component of this specialized ECM and that it is required for the structural and functional integrity of NMJs. In vivo, ColVI deficiency causes fragmentation of acetylcholine receptor (AChR) clusters, with abnormal expression of NMJ-enriched proteins and re-expression of fetal AChRγ subunit, both in Col6a1 null mice and in patients affected by Ullrich congenital muscular dystrophy (UCMD), the most severe form of ColVI-related myopathies. Ex vivo muscle preparations from ColVI null mice revealed altered neuromuscular transmission, with electrophysiological defects and decreased safety factor (i.e., the excess current generated in response to a nerve impulse over that required to reach the action potential threshold). Moreover, in vitro studies in differentiated C2C12 myotubes showed the ability of ColVI to induce AChR clustering and synaptic gene expression. These findings reveal a novel role for ColVI at the NMJ and point to the involvement of NMJ defects in the etiopathology of ColVI-related myopathies.

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Acknowledgements

We are grateful to R. Wagener for the 3(VI) antibody and Dr M. Vitadello for the neurofilament antibody. We also acknowledge support from Telethon Genetic BioBank (GTB12001D) and the Eurobiobank network. This work was supported by Italian Ministry of Education, University and Research (Grants RBAP11Z3YA_003 and 2015FBNB5Y), Telethon Foundation (Grant GGP14202) and University of Padova (to P.B.); Cariparo Foundation (Starting Grants 2015) (to M.C. and P.B.); German Research Council DFG (Grant HA3309/3-1) and Interdisciplinary Centre for Clinical Research at the University Hospital of the Friedrich-Alexander University of Erlangen-Nürnberg (Grant E17) (to S.H.). I.G. was supported by a PhD fellowship from the Cariparo Foundation.

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Authors and Affiliations

  1. Department of Molecular Medicine, University of Padova, Via Ugo Bassi 58/B, 35131, Padua, Italy

    Matilde Cescon, Ilaria Gregorio & Paolo Bonaldo

  2. Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany

    Nane Eiber & Said Hashemolhosseini

  3. Department of Neurosciences, University of Padova, 35129, Padua, Italy

    Doriana Borgia, Aurora Fusto & Elena Pegoraro

  4. IOR-IRCCS, 40136, Bologna, Italy

    Patrizia Sabatelli

  5. Institute of Molecular Genetics, National Research Council of Italy, 40136, Bologna, Italy

    Patrizia Sabatelli

  6. Department of Biomedical Sciences, University of Padova, 35121, Padua, Italy

    Michele Scorzeto & Aram Megighian

  7. CRIBI Biotechnology Center, University of Padova, Padua, 35121, Italy

    Paolo Bonaldo

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Correspondence to Matilde Cescon or Paolo Bonaldo.

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Cescon, M., Gregorio, I., Eiber, N. et al. Collagen VI is required for the structural and functional integrity of the neuromuscular junction. Acta Neuropathol 136, 483–499 (2018). https://doi.org/10.1007/s00401-018-1860-9

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  • DOI: https://doi.org/10.1007/s00401-018-1860-9

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