Blocking p62-dependent SMN degradation ameliorates spinal muscular atrophy disease phenotypes

Abstract

Spinal muscular atrophy (SMA), a degenerative motor neuron (MN) disease, caused by loss of functional survival of motor neuron (SMN) protein due to SMN1 gene mutations, is a leading cause of infant mortality. Increasing SMN levels ameliorates the disease phenotype and is unanimously accepted as a therapeutic approach for patients with SMA. The ubiquitin/proteasome system is known to regulate SMN protein levels; however, whether autophagy controls SMN levels remains poorly explored. Here, we show that SMN protein is degraded by autophagy. Pharmacological and genetic inhibition of autophagy increases SMN levels, while induction of autophagy decreases these levels. SMN degradation occurs via its interaction with the autophagy adapter p62 (also known as SQSTM1). We also show that SMA neurons display reduced autophagosome clearance, increased p62 and ubiquitinated proteins levels, and hyperactivated mTORC1 signaling. Importantly, reducing p62 levels markedly increases SMN and its binding partner gemin2, promotes MN survival, and extends lifespan in fly and mouse SMA models, revealing p62 as a potential new therapeutic target for the treatment of SMA.

Mechanisms of exercise‐induced survival motor neuron expression in the skeletal muscle of spinal muscular atrophy‐like mice

“…; Rodriguez‐Muela et al . ). The activation of autophagy is critical for mediating exercise training‐induced adaptations in healthy animals (Lira et al .…”

“…; Rodriguez‐Muela et al . ). These transcriptional and post‐translational mechanisms of SMN expression are dysregulated in SMA, the correction of which may serve as potential therapeutic targets to mitigate the SMA pathology (Biondi et al .…”

“…; Rodriguez‐Muela et al . ). While elevating SMN expression in central tissues, in particular the spinal cord and brain, improves health‐ and lifespan of SMA‐like mice, the optimal mitigation of the pathology additionally requires augmented SMN levels in peripheral tissues (Hua et al .…”

“…For example, transcriptional factors such as ETS-like gene 1 (ELK1) and cAMP response element-binding protein (CREB) have been shown to repress and drive SMN expression from SMN2, respectively (Biondi et al 2008(Biondi et al , 2015. In addition, cellular SMN levels are regulated by protein degradation processes, such as the ubiquitin-proteasome and autophagy systems, which serve to dismantle dysfunctional molecules (Han et al 2012;Kwon et al 2013;Rodriguez-Muela et al 2018). These transcriptional and post-translational mechanisms of SMN expression are dysregulated in SMA, the correction of which may serve as potential therapeutic targets to mitigate the SMA pathology (Biondi et al 2008(Biondi et al , 2015Deguise et al 2016;Rodriguez-Muela et al 2018).…”

“…In addition, cellular SMN levels are regulated by protein degradation processes, such as the ubiquitin-proteasome and autophagy systems, which serve to dismantle dysfunctional molecules (Han et al 2012;Kwon et al 2013;Rodriguez-Muela et al 2018). These transcriptional and post-translational mechanisms of SMN expression are dysregulated in SMA, the correction of which may serve as potential therapeutic targets to mitigate the SMA pathology (Biondi et al 2008(Biondi et al , 2015Deguise et al 2016;Rodriguez-Muela et al 2018). While elevating SMN expression in central tissues, in particular the spinal cord and brain, improves health-and lifespan of SMA-like mice, the optimal mitigation of the pathology additionally requires augmented SMN levels in peripheral tissues (Hua et al 2011(Hua et al , 2015.…”