Inflammation, Infections May Contribute to Severe SMA, Mouse Study Shows

Systemic inflammation and bacterial infections may be key in the progression of spinal muscular atrophy (SMA), according to a recent mouse study.

The research, “A severe mouse model of spinal muscular atrophy develops early systemic inflammation,” was published in the journal Human Molecular Genetics.

SMA is caused by mutations in the SMN1 gene, which lead to reduced production of the survival motor neuron (SMN) protein. While a second survival motor neuron gene (SMN2) is also capable of producing SMN protein, a slight difference in its DNA sequence leads to a genetic event called alternative splicing (editing) and 90 percent of the resulting SMN is shorter and nonfunctional.

While degeneration of motor nerve cells and subsequent muscle atrophy are hallmarks of SMA, increasing evidence from patients and animal models suggests the involvement of several other tissues and organs, such as the spleen, pancreas, thymus, and liver.

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The liver, known to be involved in immune and inflammatory responses, has been shown to affect the central nervous system — the brain and spinal cord. Also, massive impairment of liver-associated genes has been found in a mouse model of a severe form of SMA. As such, the liver could play a role in the development of SMA.

Chinese researchers extensively evaluated these liver defects, their causes, and their effects on other tissues in the mouse model.

They found that the mice not only had liver-associated inflammation, but also inflammation throughout the body — systemic inflammation — in early stages of the disease.

Because systemic or chronic inflammation has been associated with several neurodegenerative diseases and nerve cell death, this SMA-associated systemic inflammation may contribute to the worsening of SMA and accelerate its progression.

Inflammation was found to be partly caused by a damaged intestinal barrier, which allowed pathogens to enter the bloodstream and organs, including the liver.

These mice were also significantly more vulnerable to bacterial infections and died faster than healthy mice. This type of infection was found to affect SMN2 splicing, suppressing the production of functional SMN protein and leading to lower SMN levels in the liver, heart, and central nervous system.

These findings suggest that systemic inflammation induced by bacterial infections worsens as the disease progresses, and results in even lower production of SMN from the SMN2 gene, aggravating SMA disease.

The team also re-analyzed 154 blood markers previously identified in SMA patients with regression in their motor function, and found that 57 of them were involved in inflammatory responses, suggesting that systemic inflammation also occurs in SMA patients.

“Our data not only identifies an important mechanism that deteriorates SMA … through multiple molecular paths but also provides explanations for multiple phenomena and gene expression abnormalities in severe SMA mice that perplex researchers,” the team said. Gene expression is the process by which information in a gene is synthesized to create a working product, such as a protein.

The team also noted that these results may help to better understand the development of SMA, particularly the severe forms, and that additional research on the mechanisms behind the control of SMN2 splicing by bacterial infections or resulting inflammatory responses may lead to new therapeutic targets and approaches.