title: Label-free quantitative proteomic profiling identifies disruption of ubiquitin homeostasis as a key driver of Schwann cell defects in spinal muscular atrophy.
abstract: Low levels of survival of motor neuron (SMN) protein cause the neuromuscular disease spinal muscular atrophy (SMA), characterized by degeneration of lower motor neurons and atrophy of skeletal muscle. Recent work demonstrated that low levels of SMN also trigger pathological changes in Schwann cells, leading to abnormal axon myelination and disrupted deposition of extracellular matrix proteins in peripheral nerve. However, the molecular pathways linking SMN depletion to intrinsic defects in Schwann cells remained unclear. Label-free proteomics analysis of Schwann cells isolated from SMA mouse peripheral nerve revealed widespread changes to the Schwann cell proteome, including disruption to growth/proliferation, cell death/survival, and molecular transport pathways. Functional clustering analyses revealed significant disruption to a number of proteins contributing to ubiquitination pathways, including reduced levels of ubiquitin-like modifier activating enzyme 1 (Uba1). Pharmacological suppression of Uba1 in Schwann cells was sufficient to reproduce the defective myelination phenotype seen in SMA. These findings demonstrate an important role for SMN protein and ubiquitin-dependent pathways in maintaining Schwann cell homeostasis and provide significant additional experimental evidence supporting a key role for ubiquitin pathways and, Uba1 in particular, in driving SMA pathogenesis across a broad range of cells and tissues.
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh , Edinburgh EH8 9XD, United Kingdom.
authors.forename: Arwin
authors.initials: A
authors.lastname: Aghamaleky Sarvestany
authors.forename: Gillian
authors.initials: G
authors.lastname: Hunter
authors.forename: Amy
authors.initials: A
authors.lastname: Tavendale
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Lamont
authors.forename: Maica
authors.initials: M
authors.lastname: Llavero Hurtado
authors.forename: Laura C
authors.initials: LC
authors.lastname: Graham
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wishart
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Gillingwater
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D006706:Homeostasis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009134:Muscular Atrophy, Spinal / Q000378:metabolism* / Q000473:pathology*; D010525:Peripheral Nerves / Q000166:cytology / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology*; D025801:Ubiquitin / Q000378:metabolism*; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors
chemical_list: D025801:Ubiquitin; D044764:Ubiquitin-Activating Enzymes
keywords: SMA; Schwann cell; label-free proteomics; mouse; spinal muscular atrophy; uba1; ubiquitin