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

Matilde Cescon, Ilaria Gregorio, Nane Eiber, Doriana Borgia, Aurora Fusto, Patrizia Sabatelli, Michele Scorzeto, Aram Megighian, Elena Pegoraro, Said Hashemolhosseini, Paolo Bonaldo

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)483-499
Number of pages17
JournalActa Neuropathologica
Volume136
Issue number3
DOIs
Publication statusE-pub ahead of print - May 11 2018

Keywords

  • Bethlem myopathy
  • Collagen VI
  • Extracellular matrix
  • Neuromuscular junction
  • Synaptic cleft
  • Ullrich congenital muscular dystrophy

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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