Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy

Abstract

The autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) results from low levels of survival motor neuron (SMN) protein; however, it is unclear how reduced SMN promotes SMA development. Here, we determined that ubiquitin-dependent pathways regulate neuromuscular pathology in SMA. Using mouse models of SMA, we observed widespread perturbations in ubiquitin homeostasis, including reduced levels of ubiquitin-like modifier activating enzyme 1 (UBA1). SMN physically interacted with UBA1 in neurons, and disruption of Uba1 mRNA splicing was observed in the spinal cords of SMA mice exhibiting disease symptoms. Pharmacological or genetic suppression of UBA1 was sufficient to recapitulate an SMAlike neuromuscular pathology in zebrafish, suggesting that UBA1 directly contributes to disease pathogenesis. Dysregulation of UBA1 and subsequent ubiquitination pathways led to β-catenin accumulation, and pharmacological inhibition of β-catenin robustly ameliorated neuromuscular pathology in zebrafish, Drosophila, and mouse models of SMA. UBA1-associated disruption of β-catenin was restricted to the neuromuscular system in SMA mice; therefore, pharmacological inhibition of β-catenin in these animals failed to prevent systemic pathology in peripheral tissues and organs, indicating fundamental molecular differences between neuromuscular and systemic SMA pathology. Our data indicate that SMA-associated reduction of UBA1 contributes to neuromuscular pathogenesis through disruption of ubiquitin homeostasis and subsequent β-catenin signaling, highlighting ubiquitin homeostasis and β-catenin as potential therapeutic targets for SMA.

Emerging therapies and challenges in spinal muscular atrophy

“…Consequently, SMN deficiency may impair targeting and local translation of axonal mRNAs essential for motor neuron development and maintenance 44, 45. Furthermore, SMN regulates several other fundamental cellular processes in the neuronal cytoplasm that are critical for maintaining axonal and synaptic health, including endocytic pathways, local translation, mitochondrial transport, and targeting to axons and ubiquitin homeostasis 46, 47, 48, 49, 50, 51…”

Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: implications for spinal muscular atrophy

“…Dominant mutations in GARS cause the distal neuropathy Charcot-MarieTooth disease type 2D, and recent observations suggest that GARS may colocalize with SMN in human cells (Motley et al 2010;Drew et al 2011;Grice et al 2015). Mouse models of SMA exhibit disruptions to ubiquitin homeostasis, and evidence of SMN interactions with proteasomal components, including Psmd1, the mouse ortholog of Drosophila Rpn2 (Aghamaleky Sarvestany et al 2014;Wishart et al 2014).…”

Vascular Defects and Spinal Cord Hypoxia in Spinal Muscular Atrophy

“…4,5 However, similar defects have been unmasked when therapies specifically targeting the motor system resulted in significant improvement of motor skills, but failed to rescue overall disease severity in SMA mice. [6][7][8] Furthermore, recent work using peripherally targeted rescue strategies has demonstrated that therapies that specifically do not modulate SMN protein levels in the central nervous system (CNS) are still able to significantly ameliorate disease severity in SMA mice. 9,10 The role that the cardiovascular system, and blood vessels in particular, play in SMA pathogenesis remains unclear.…”