A common mechanism behind muscle wasting and motor neuron degeneration in ALS?

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons and severe muscle atrophy without effective treatment. ALS patients display a strong muscle phenotype, including progressive atrophy and wasting, sharing some mechanisms with other neuromuscular diseases including age-induced sarcopenia. Actually, many of the alterations that take place in the CNS, and especially in the motor neurons, are replicated in the skeletal muscle

Yet most research on ALS has been focused on the study of motor neurons and supporting cells of the central nervous system. This is a bit astonishing as several lines of evidence suggest that muscle turnover is impaired in ALS, suggesting a common mechanism for degeneration of motor neurons and squeletal muscles. A fine-tuning balance between biosynthetic and atrophic pathways is necessary to maintain homeostasis in muscle tissue, the same is true for the many cells types that are collectively called "glia".

Muscle atrophy generally occurs due to an imbalance in proteostasis, where protein degradation exceeds protein synthesis and results in loss of contractile proteins and shrinkage of myofibers, which ultimately lead to loss of muscle mass and muscle weakness. At the molecular level, muscle fiber atrophy can be attributed to different signaling pathways, which are relevant to the abnormality of protein degradation. Indeed, protein aggregates with TDP-43, neurofilament, FUS, or SOD1, which are detected in the vast majority of ALS patients, can appear in the cytoplasm of neurons and within the skeletal muscle, suggesting an imbalance between protein synthesis and degradation pathways. In fact, there is solid evidence that defects in the two major protein clearance pathways, the UPS and the autophagy, mediate such dysregulated protein homeostasis and can be central components of the disease mechanisms in ALS.

This review does not explore the hypothesis that there is a common mechanism behind muscle wasting and motor neuron degeneration due to glia dysfunctions. Instead it provides a comprehensive analysis on the current state-of-the-art of the role of the skeletal muscle in ALS, highlighting its contribution to the neurodegeneration in ALS through backward-signaling processes as a newly uncovered mechanism for a peripheral etiopathogenesis of the disease.

Yet the notion that ALS is not strictly a disease of motor neurons is enough innovative to be mentioned in this blog.

I would welcome comments on this notion at : contact at padiracinnovation.org



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