Mutations in the survival motor neuron 1 gene (SMN1), which result in reduced expression and lower levels of the full-length SMN protein, are responsible for spinal muscular atrophy (SMA).1 Given the role that microRNAs (miRNAs) play in gene expression, it is perhaps not surprising that they are implicated in this hereditary disease. The potential ways that miRNAs are involved in the pathogenesis of SMA are just beginning to be identified.Â
SMA primarily affects spinal motor neurons, which are cells of the nervous system that reside in the spine and control muscle movement.1 The long-term survival of these cells is also critically dependent on miRNAs. miRNAs are required for the normal development and differentiation of spinal motor neurons, as well as the ability of these cells to grow axons and form synapses.2–7 Specific miRNAs function differently in spinal motor neurons and at different times during development and so likely contribute to SMA pathogenesis in distinct ways. Below are some of the miRNAs that appear involved in SMA.
miRNA-9
miRNA-9 regulates neuronal function and can be found in abundance throughout the central nervous system.1 The potential role of miRNA-9 in SMA was revealed in 2010 when it was observed that abnormal miRNA-9 biogenesis was associated with a phenotype in mice that resembled SMA.8 Further investigation has shown that the lower levels of full-length SMN protein that occur in SMA alter miRNA-9 levels. Indeed, when SMN expression is upregulated, miRNA-9 expression returns to normal.1
miRNA-132
Like miRNA-9, miRNA-132 is abundant in the central nervous system. This miRNA also follows a similar pattern of tissue gene expression as miRNA-9.1 The primary roles of miRNA-132 involve synaptic function and the outgrowth of neuronal dendrites.9,10 This miRNA is implicated in the vascular defects seen in models of SMA.11–13                     Â
miRNA-2
miRNA-2 is upregulated in the early stages of SMA, which is thought to potentially contribute to the dysfunction observed in motor neurons in this disease.1 The upregulation of miRNA-2 has been shown to lead to a 50% increase in miRNA-2 expression levels in mouse models of SMA. When this miRNA is inhibited pharmacologically, motor neuron function returns to normal.
miRNA-375
miRNA-375 is involved in the development of motor neurons, making it a likely contender for SMA involvement14 This miRNA is indeed activated at high rates while spinal motor neurons are being generated, and this pattern of activation is specific to motor neurons. Research has shown that exogenous expression of miRNA-375 can prevent types of apoptosis in motor neurons in models of SMA, which suggests that miRNA-375 may provide a therapeutic target for SMA.1,15 Â Â
miRNA-183
Consistent with the idea that miRNA-183 is involved with SMA, researchers have shown that miRNA-183 is higher in neurons that are deficient in survival motor neuron protein, specifically in the neurites.16 Further, inhibiting this miRNA in the spinal cord of animal models of SMA have been shown to improve motor function and lengthen survival in these models.Â
miRNA-206
miRNA-206 has been implicated in multiple neuromuscular disorders, including SMA and amyotrophic lateral sclerosis (ALS) and appears to be dysregulated in both of these diseases.1 Because this miRNA is able to at least partially delay the process of neurodegeneration, it could provide a therapeutic target for SMA and other neuromuscular disorders.
miRNA-146
miRNA-146 is another miRNA that may be involved in SMA. Data on the role of this miRNA in SMA suggest that astrocyte production of miRNA-146a may be altered in SMA and thereby contribute to SMA pathogenesis.17–19 One way this alteration could impact motor neurons is through changes in NFκB signaling.Â
Research into the specific roles of distinct miRNAs in SMA is likely to improve our understanding of the pathogenesis of SMA as well as potential ways to treat the symptoms or the underlying cause of the disease.
References
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16. Kye MJ, Niederst ED, Wertz MH, et al. SMN regulates axonal local translation via miRNA-183/mTOR pathway. Hum Mol Genet. 2014;23(23):6318-6331. doi:10.1093/hmg/ddu350
17. Sison SL, Patitucci TN, Seminary ER, Villalon E, Lorson CL, Ebert AD. Astrocyte-produced miRNA-146a as a mediator of motor neuron loss in spinal muscular atrophy. Hum Mol Genet. 2017;26(17):3409-3420. doi:10.1093/hmg/ddx230
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19. Kumar A, Kopra J, Varendi K, et al. GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function. PLoS Genet. 2015;11(12):e1005710. doi:10.1371/journal.pgen.1005710