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.

Restoration of SMN in Schwann cells reverses myelination defects and improves neuromuscular function in spinal muscular atrophy

“…Taken together, these findings support the hypothesis that myelination defects in SMA result from direct, intrinsic deficiencies in Schwann cells, rather than occurring as a secondary consequence to pathology in neighbouring motor neurons (32,33). …”

“…Glial cells from the peripheral nervous system (PNS) have also been implicated in SMA, with changes observed in non-myelinating terminal Schwann cells in several different SMA mouse models (29–31). Similarly, in vivo and in vitro analyses of myelinating Schwann cells demonstrated intrinsic defects in SMA (evidenced by SMN-dependent failure of isolated SMA-derived Schwann cells to respond to myelination cues), leading to defects in myelination and generation of extracellular matrix in peripheral nerve (32,33). …”

Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

“…To understand how SMN deficiency can disrupt Schwann cell physiological functions, Sarvestany and collaborators (2014) (Table 1) performed label-free proteomics analyses of Schwann cells obtained from SMA mouse peripheral nerve [90]. Through this approach, they found that several pathways were altered in SMA Schwann cells including growth, proliferation, cell death, survival and molecular transport.…”

“…Of particular interest, functional cluster analysis revealed that ubiquitination pathways are profoundly disrupted in SMN-deficient Schwann cells. For example, reduced levels of ubiquitin-like modifier activating enzyme 1 (uba1) were observed [90]. In fact, suppression of Uba1 through pharmacological treatment in WT Schwann cells is sufficient to recapitulate the defective myelination phenotype presented by SMA Schwann cells [90].…”

“…For example, reduced levels of ubiquitin-like modifier activating enzyme 1 (uba1) were observed [90]. In fact, suppression of Uba1 through pharmacological treatment in WT Schwann cells is sufficient to recapitulate the defective myelination phenotype presented by SMA Schwann cells [90]. Microarrary analyses of Schwann cell myelination-related genes revealed disrupted gene expression in tissue from SMA mice in comparison to WT [87,88].…”