Pathogenic commonalities between spinal muscular atrophy and amyotrophic lateral sclerosis: Converging roads to therapeutic development

Abstract

Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are the two most common motoneuron disorders, which share typical pathological hallmarks while remaining genetically distinct. Indeed, SMA is caused by deletions or mutations in the survival motor neuron 1 (SMN1) gene whilst ALS, albeit being mostly sporadic, can also be caused by mutations within genes, including superoxide dismutase 1 (SOD1), Fused in Sarcoma (FUS), TAR DNA-binding protein 43 (TDP-43) and chromosome 9 open reading frame 72 (C9ORF72). However, it has come to light that these two diseases may be more interlinked than previously thought. Indeed, it has recently been found that FUS directly interacts with an Smn-containing complex, mutant SOD1 perturbs Smn localization, Smn depletion aggravates disease progression of ALS mice, overexpression of SMN in ALS mice significantly improves their phenotype and lifespan, and duplications of SMN1 have been linked to sporadic ALS. Beyond genetic interactions, accumulating evidence further suggests that both diseases share common pathological identities such as intrinsic muscle defects, neuroinflammation, immune organ dysfunction, metabolic perturbations, defects in neuron excitability and selective motoneuron vulnerability. Identifying common molecular effectors that mediate shared pathologies in SMA and ALS would allow for the development of therapeutic strategies and targeted gene therapies that could potentially alleviate symptoms and be equally beneficial in both disorders. In the present review, we will examine our current knowledge of pathogenic commonalities between SMA and ALS, and discuss how furthering this understanding can lead to the establishment of novel therapeutic approaches with wide-reaching impact on multiple motoneuron diseases.

Muscle overexpression of Klf15 via an AAV8-Spc5-12 construct does not provide benefits in spinal muscular atrophy mice

“…Skeletal muscle with reduced levels of SMN displays both cell-autonomous and non-autonomous defects [16,17] and is therefore an important therapeutic target for SMA. We have recently demonstrated the dysregulated expression of the transcription factor Krüppel-like factor 15 (Klf15) in skeletal muscle of SMA mice during disease progression [18].…”

Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases

“…Studies have shown that a series of genetic mutations are associated with ALS [ 172 , 173 ]. Mutations such as the Cu/Zn-dependent superoxide dismutase 1 (SOD1) gene caused loss of dynein function, leading to the accumulation of pathological protein aggregates in ALS [ 174 , 175 , 176 , 177 ]. Studies have shown that genetic mutations enhanced the binding of autophagy matrix to autophagosomes through interaction with LC3 [ 178 , 179 , 180 ].…”

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

“…1J), we sought to identify the causes of the swimming and paralysis phenotypes. We have shown in previous work that neurotransmission is affected in C. elegans models of ALS, and since ALS and SMA are very similar clinically (22) we tested synaptic function in smn-1(gk) animals. Upon treatment with aldicarb, an acetylcholinesterase inhibitor (23), smn-1 mutant worms displayed a hypersensitivity and paralyzed sooner than control animals, but not to the extent of unc-47(e307) positive control animals ( Fig.…”