Abstract
Spinal muscular atrophy (SMA) is the most common genetic disease causing infant death, due to an extended loss of motoneurons. This neuromuscular disorder results from deletions and/or mutations within the Survival Motor Neuron 1 (SMN1) gene, leading to a pathological decreased expression of functional full-length SMN protein. Emerging studies suggest that the small GTPase RhoA and its major downstream effector Rho kinase (ROCK), which both play an instrumental role in cytoskeleton organization, contribute to the pathology of motoneuron diseases. Indeed, an enhanced activation of RhoA and ROCK has been reported in the spinal cord of an SMA mouse model. Moreover, the treatment of SMA mice with ROCK inhibitors leads to an increased lifespan as well as improved skeletal muscle and neuromuscular junction pathology, without preventing motoneuron degeneration. Although motoneurons are the primary target in SMA, an increasing number of reports show that other cell types inside and outside the central nervous system contribute to SMA pathogenesis. As administration of ROCK inhibitors to SMA mice was systemic, the improvement in survival and phenotype could therefore be attributed to specific effects on motoneurons and/or on other non-neuronal cell types. In the present review, we will present the various roles of the RhoA/ROCK pathway in several SMA cellular targets including neurons, myoblasts, glial cells, cardiomyocytes and pancreatic cells as well as discuss how ROCK inhibition may ameliorate their health and function. It is most likely a concerted influence of ROCK modulation on all these cell types that ultimately lead to the observed benefits of pharmacological ROCK inhibition in SMA mice.
Highlights
Spinal muscular atrophy (SMA) is a devastating neurodegenerative disease, affecting approximately 1:6,000–10,000 live births per year (Pearn, 1978; Crawford and Pardo, 1996)
While SMA is undeniably primarily a motoneuron disease, a growing number of studies have reported defects in other cell types and organs, whether they be within the CNS such as glial cells, or outside, like the pancreas, heart or skeletal muscle
The development of systemic therapeutic approaches such as ROCK inhibition has further emphasized the need to further understand the contribution of multiple cell types in this pathology
Summary
Spinal muscular atrophy (SMA) is a devastating neurodegenerative disease, affecting approximately 1:6,000–10,000 live births per year (Pearn, 1978; Crawford and Pardo, 1996). ROCK inhibition and SMA et al, 2000), Smn−/−; SMN2; SMN 7/ 7 (Le et al, 2005) and Smn2B/− mice (Hammond et al, 2010; Bowerman et al, 2012a) and range from severe (death within the first post-natal week) to intermediate phenotypes (average lifespan of 30 days) In spite of these differences in survival times, all of these models display spinal cord motoneuron degeneration, muscle atrophy as well as neuromuscular junction (NMJ) defects and have been indispensable in our understanding of the disease and in the evaluation of potential therapeutic approaches. We will discuss the potential cellular targets that may participate in the beneficial effect of ROCK inhibition in SMA mice, To this aim, the role of the RhoA/ROCK pathway in healthy cells and in SMA pathology will be analyzed (Figure 1) and we will elaborate on how the systemic modulation of ROCK could influence these cells and tissues, and potentially the course of the disease (Figure 2)
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