Label-Free Quantitative Proteomic
Profiling Identifies
Disruption of Ubiquitin Homeostasis As a Key Driver of Schwann Cell
Defects in Spinal Muscular Atrophy
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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