Label-free quantitative proteomic profiling identifies disruption of ubiquitin homeostasis as a key driver of schwann cell defects in spinal muscular atrophy

Arwin Aghamaleky Sarvestany, Gillian Hunter, Amy Tavendale, Douglas Lamont, Maica Llavero Hurtado, Laura Graham, Thomas Wishart, Thomas Gillingwater

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)4546-4557
Number of pages12
JournalJournal of Proteome Research
Volume13
Issue number11
Early online date29 Aug 2014
DOIs
Publication statusPublished - 2014

Keywords

  • proteomic profiling
  • spinal muscular atrophy
  • motor neurons

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