The VAPB/ALS8 major sperm protein domain (vMSP) is implicated in amyotrophic lateral sclerosis and spinal muscular atrophy, yet its function in the nervous system is not well understood. In Caenorhabditis elegans and Drosophila, the vMSP is cleaved fromits transmembrane anchor and secreted ina cell type-specific fashion. We show that vMSPs secreted by neurons act on Lar-like protein-tyrosine phosphatase and Roundabout growth cone guidance receptors expressed in striated muscle. This signaling pathway promotes Arp2/3-dependent actin remodeling and mitochondrial localization to actin-rich muscle I-bands. C.elegans VAPB mutants have mitochondrial localization, morphology, mobility, and fission/fusion defects that are suppressed byLar-like receptor or Arp2/3 inactivation. Hence, growth cone guidance receptor pathways that remodel the actin cytoskeleton have unanticipated effects on mitochondrial dynamics. We propose that neurons secrete vMSPs to promote striated muscle energy production and metabolism, in part through the regulation of mitochondrial localization and function. Video Abstract: Mutations in MSP domain proteins cause the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Han etal. show that neurons secrete the MSP domain to control Robo/Lar signaling in muscle. Downstream effects on cortical actin influence muscle mitochondrial dynamics and function, consistent with ALS and SMA.
ASJC Scopus subject areas
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Developmental Biology
- Cell Biology