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Abstract
Spinal muscular atrophy (SMA) is an inherited neuromuscular disease primarily characterized by degeneration of spinal motor neurons, and caused by reduced levels of the SMN protein. Previous studies to understand the proteomic consequences of reduced SMN have mostly utilized patient fibroblasts and animal models. We have derived human motor neurons from type I SMA and healthy controls by creating their induced pluripotent stem cells (iPSCs). Quantitative mass spectrometry of these cells revealed increased expression of 63 proteins in control motor neurons compared to respective fibroblasts, whereas 30 proteins were increased in SMA motor neurons vs. their fibroblasts. Notably, UBA1 was significantly decreased in SMA motor neurons, supporting evidence for ubiquitin pathway defects. Subcellular distribution of UBA1 was predominantly cytoplasmic in SMA motor neurons in contrast to nuclear in control motor neurons; suggestive of neurodevelopmental abnormalities. Many of the proteins that were decreased in SMA motor neurons, including beta III-tubulin and UCHL1, were associated with neurodevelopment and differentiation. These neuron-specific consequences of SMN depletion were not evident in fibroblasts, highlighting the importance of iPSC technology. The proteomic profiles identified here provide a useful resource to explore the molecular consequences of reduced SMN in motor neurons, and for the identification of novel biomarker and therapeutic targets for SMA.
Highlights
Spinal Muscular Atrophy (SMA) is a recessively inherited neuromuscular disease displaying a wide range of severity, from the most severe Type I, to adult onset, Type IV
Human induced pluripotent stem cells (iPSCs)-derived motor neurons were used to identify motor neuron-specific down-stream effects of reduced survival of motor neurons (SMN), not found in fibroblasts, which may help to explain the particular vulnerability of motor neurons in Spinal muscular atrophy (SMA)
In addition to reduced levels of ubiquitin-activating enzyme 1 (UBA1), we observed differential distribution within the cells, whereby the majority of UBA1 was localized in the cytoplasm in SMA motor neurons, in contrast to the mainly nuclear distribution seen in control motor neurons
Summary
Spinal Muscular Atrophy (SMA) is a recessively inherited neuromuscular disease displaying a wide range of severity, from the most severe Type I (diagnosed somewhere between birth to 6 months of age), to adult onset, Type IV. SMN is a ubiquitously-expressed protein that plays a central role RNA biogenesis; regulating the assembly of small nuclear ribonucleic proteins (snRNPs) in the cytoplasm and their subsequent transport into the nucleus (Lefebvre et al, 1995; Pellizzoni et al, 1998) Aside from this housekeeping role, SMN appears to have a neuronal-specific role in mRNA processing, where it interacts with hnRNP-R to transport βactin mRNA in axons (Rossoll et al, 2003; Carrel et al, 2006). Despite this knowledge about the cellular functions of SMN, it has become clear, from studies with mouse models, that defects in RNA splicing or axonal transport do not fully explain why lower motor neurons are vulnerable to reduced levels of SMN (Kariya et al, 2008; Burghes and Beattie, 2009; Murray et al, 2010; Sleigh et al, 2011; Hamilton and Gillingwater, 2013)
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