Researchers Highlight Emerging Concepts Underlying Selective Neuromuscular Dysfunction in SMA

A group of researchers has outlined available evidence for emerging molecular and cellular mechanisms that have been implicated in selective neuromuscular dysfunction in infantile spinal muscular atrophy (SMA).

Conducting a review of published data over a 25-year period, the researchers highlight the importance of this type of research they say offers insight that drives the success of SMA treatment. Their findings appear in Neural Regeneration Research.

A bucket of research highlighted by the group offers a look into why proximally innervating motor neurons are selectively vulnerable in SMA. Based on this research, p53 signaling has emerged as an important driver of the neurodegenerative phenotype of SMA. Although research has backed p53 as being linked to activity in the severe form of SMA, as well as its stabilization and activation through degradation of short-lived, alternatively spliced Mdm2/4 gene products, it remains undetermined if, and to what extent, the pathway and its activation play a role with motor neuron loss in intermediate and milder forms of disease.

“Despite the varying degrees to which motor neuron loss and motor behavior are attenuated by restoring SMN [survival of motor neuron]–dependent splicing abnormalities and preventing p53 activation, denervation in the SMA mice proceeds unimpeded and animals rapidly succumb to disease,” wrote the researchers. “Clearly then, blocking p53 activation and/or restoring levels of the minor spliceosome are insufficient to confer more than a modest degree of protection from low SMN.”

As a result, the SMA community has explored other disease-relevant SMN functions, with research from as early as 2003 suggesting that there’s a role for SMN in assembling other RNP complexes. According to the researchers of the review, SMN plays an important role as a chaperone of messenger ribonucleoproteins (mRNPs), as SMA is linked to fewer and smaller mRNP granules and a reduced association of granules with molecular motors involved in axonal transport of locally regulated transcripts and their protein products.

A third bucket of research the investigators highlighted focuses on the role of the neuromuscular junction (NMJ). One analysis of the timing of the emergence of motor unit defects in several mouse models of severe SMA revealed that defects at the NMJ precede deafferentiation and motor neuron body loss. Research has also shown that controlled depletion of SMN during childhood drives NMJ defects without evidence of motor neuron defects or loss in the spinal cord.

“These and other investigations have long argued for a role for the SMN protein in both the early postnatal development and later maintenance of the NMJ,” wrote the researchers. “One set of results that supports this proposition stems from a revealing series of investigations into the causes of discordant phenotypes in [siblings] with identical 5q. The outcomes of these studies make a compelling case for a role for the SMN protein in ensuring proper neurotransmission at the NMJ by regulating the process of endocytosis.”

Reference

Gollapalli K, Kim J, Monani U. Emerging concepts underlying selective neuromuscular dysfunction in infantile-onset spinal muscular atrophy. Neural Regen Res. 2021;16(10)1978-1984. doi: 10.4103/1673-5374.308073