Molecular changes appear before ALS symptoms in SOD1 mouse model

Molecular changes linked to inflammation and how brain cells process proteins and genetic material may occur before the onset of amyotrophic lateral sclerosis (ALS) symptoms, a study in a mouse model of SOD1-related ALS suggests.

The findings also point to changes in the hypothalamus, a brain region involved in appetite and energy regulation, that may be related to metabolic changes associated with ALS.

“[Presymptomatic ALS mouse model] may serve as an important model for studying the early mechanisms of the disease and potential intervention strategies,” the researchers wrote.

Recommended Reading

Sept. 22, 2026 News by Steve Bryson, PhD

Researchers identify 10 genes that may help diagnose, track ALS 

Study maps early molecular changes in SOD1-related ALS

The study, “Spatial transcriptomics reveals dysregulated biological process in ALS mouse models with sod1 mutation,” was published in Scientific Reports.

ALS is caused by the progressive loss of motor neurons, the nerve cells responsible for controlling voluntary movements. Mutations in the SOD1 gene, which result in the production of an abnormal SOD1 protein, are among the most common genetic causes of ALS.

The mechanisms underlying ALS include dysfunction of the cellular machinery that regulates protein production and RNA processing, problems in the mitochondria — the cellular structures that produce energy — and inflammation. However, it remains unclear how these processes interact during ALS progression.

To investigate this, researchers used spatial transcriptomics, a technique that maps gene activity to specific locations within tissue, to analyze one brain tissue sample from each of three mice: a healthy control mouse, a mouse with a SOD1 mutation (SOD1G93A) but no ALS-like symptoms, and a mouse with the same mutation and ALS-like symptoms.

The analysis identified distinct gene activity patterns among the three samples. In the presymptomatic sample, genes with increased activity were enriched in processes related to myeloid immune-cell regulation and the breakdown of protein complexes within cells.

Symptomatic mouse shows RNA and protein-processing changes

In the symptomatic ALS sample, genes involved in RNA processing and protein production and regulation were more active. These changes affected processes involved in interpreting genetic instructions and making and managing proteins.

According to the researchers, these findings suggest that “expression levels of Sod1 are closely associated with disruptions in RNA metabolism, protein homeostasis, and inflammatory signaling.”

Among the genes that became more active in the mutant samples, Sod1, Stmn1, and Sgk1 showed some of the greatest increases. Their activity was elevated in both the presymptomatic and symptomatic samples. These findings suggest the expression levels of these genes “can serve as a potential marker for the early detection of ALS,” the researchers wrote.

Il33, a gene involved in inflammatory signaling, was also more active in the mutant samples and highest in the symptomatic sample. In that sample, its activity was higher in oligodendrocytes than in other major brain cell types. Oligodendrocytes produce myelin, a protective coating around nerve fibers that helps them send electrical signals more efficiently.

The researchers also examined how different types of brain cells differed across the three samples, including neurons and glial cells, which provide support and protection for neurons. They found that astrocytes, a type of glial cell, made up a larger proportion of cells in the presymptomatic and symptomatic samples than in the normal sample, while neurons made up a slightly smaller proportion.

The Sod1 gene was more active across all major brain cell types in the presymptomatic and symptomatic samples than in the normal sample. Motor neurons showed particularly high Sod1 activity in the symptomatic sample.

Gene activity shifts across brain cells as disease advances

There were also differences in gene activity between the symptomatic and normal samples. In the symptomatic sample, more active genes were mainly involved in RNA processing, protein synthesis, and inflammatory responses. By contrast, genes that were more active in the normal sample were involved in processes such as the development of glial cells and the maintenance of metal ion balance within cells.

“This observation indicates that the ALS group displays a heightened inflammatory response, potentially because of disruptions in RNA and protein homeostasis during the progression of ALS,” the researchers wrote.

The researchers then examined the hypothalamus, a brain region involved in regulating appetite and energy expenditure. In this region, the Sod1 gene was more active in the presymptomatic and symptomatic samples, whereas several genes involved in regulating appetite were less active than in the normal sample. The researchers suggested that these changes “may account for the significant decrease in food intake observed in ALS patients.” However, they noted that the individual appetite-related genes can have different effects, suggesting a complex balance between energy intake and expenditure in ALS.

In this brain region, the activity of genes involved in maintaining the balance of RNA and proteins within cells also increased across the normal, presymptomatic, and symptomatic samples.

“This research provides new insights into the molecular mechanisms underlying ALS,” highlighting the “widespread impact of the Sod1 mutation on various neuronal and glial cell types,” the researchers wrote. However, they noted that further studies are needed to determine whether these changes also occur in people with ALS.