Modulating the endoplasmic reticulum stress response attenuates neurodegeneration in a Caenorhabditis elegans model of spinal muscular atrophy

Abstract

Spinal muscular atrophy is (SMA) is a devastating, autosomal recessive neuromuscular disease resulting in muscle atrophy, neurodegeneration, and is the leading genetic cause of infant death. SMA arises when there are homozygous deletion mutations in the human SMN1 gene, leading to a decrease in corresponding SMN1 protein. Although SMN1 is expressed across multiple tissue types, much of the previous research into SMA focused on the neuronal aspect of the disease, overlooking many of the potential non-neuronal aspects of the disease. Therefore, we sought to address this gap in knowledge by modeling SMA in the nematode Caenorhabditis elegans. We used a previously uncharacterized allele which resulted in the onset of mild SMA-like phenotypes allowing us to monitor the onset of phenotypes at different stages. We observed that these mutant animals recapitulated many key features of the human disease, and most importantly, we observed that muscle dysfunction precedes neurodegeneration. Furthermore, we tested the therapeutic efficacy of targeting endoplasmic reticulum (ER) stress in non-neuronal cells and found it to be more effective than targeting ER stress in neuronal cells. We also found that the most potent therapeutic potential came from a combination of ER- and neuromuscular junction (NMJ)-targeting drugs. Together, our results suggest an important non-neuronal component of SMA pathology and highlight new considerations for therapeutic intervention.

The SMN-ribosome interplay: a new opportunity for Spinal Muscular Atrophy therapies

“…ER stress activates the integrated stress response (ISR) via the PERK pathway, which results in the phosphorylation of the eIF2α, inhibition of translation initiation, and overexpression of apoptotic or heat shock genes [ 112 , 113 ]. Activation of the ISR was observed in a Caenorhabditis elegans SMA model [ 113 ], in hiPSC-derived MNs from patients, and in the spinal cord of a mild mouse model of the disease [ 82 ]. Pharmacological inhibition of the ER stress exerts mild improvement in mice lifespan [ 80 ].…”

“…Among the few compounds boosting translation, ISRIB blocks the PERK branch of the unfolded protein response leading to a partial restoration of translation in prion diseases [ 132 ] and amyotrophic lateral sclerosis (ALS) [ 134 ]. As aforementioned, the activation of ISR has been observed in some models of SMA at the late symptomatic stage [ 113 , 135 ], but there is no evidence of eIF2α phosphorylation at early and late symptomatic stages in a different model [ 2 ]. Therefore, as of now, there is no clear evidence demonstrating the widespread activation of the ISR in multiple SMA models.…”

Innovating spinal muscular atrophy models in the therapeutic era

“…Finally, in animal models in which modification of the genome is challenging, such as pigs, transient knockdown of Smn1 has been induced by adeno-associated virus (AAV; Box 1 ) 9-mediated delivery of specific short harpin RNAs (shRNAs) ( Duque et al, 2015 ). In invertebrate models of SMA, synaptic defects, studied in C. elegans ( Briese et al, 2008 ; Doyle et al, 2020 ), and altered NMJ development, studied in Drosophila ( Chan et al, 2003 ), lead to defective locomotion and reduced lifespan as the most prominent disease phenotype. Moreover, Drosophila are relatively suitable for studying intermediate SMA phenotypes, as Smn loss-of-function mutations can be used to reliably generate animals with varying degrees of phenotypic severity and survival ( Spring et al, 2019 ).…”

“…The success story of SMA therapies was built, in large part, on the availability of multiple, robust disease models ranging from cell-based models to small animals ( Table 1 ) – such as Caenorhabditis elegans ( Briese et al, 2008 ; Doyle et al, 2020 ; Sleigh et al, 2011a ), Drosophila ( Chan et al, 2003 ; Chang et al, 2008 ; Spring et al, 2019 ) and zebrafish ( Boon et al, 2009 ; McWhorter et al, 2003 ; Tay et al, 2021 ) – and many mouse models ( Table 2 ) ( Bowerman et al, 2009 , 2012a ; Hsieh-Li et al, 2000 ; Le et al, 2005 ; Monani et al, 2000 ). These models allowed key aspects of SMA pathology to be characterised and gene-targeting therapies to be investigated, tested and optimised in vitro and in vivo.…”