ALS Inflammation Expression Sheds Light on Potential Treatment Approaches


Intracellular receptor protects against the negative effects of inflammation in ALS.

Amyotrophic lateral sclerosis (ALS) patients have a higher expression of IP3R2 in their blood. While investigating the relevance of this high expression, researchers were surprised to find that IP3R2 acts as a protector against the negative effects of inflammation in ALS.

In a study published in Human Molecular Genetics, researchers used mouse models of ALS that had mutations in the gene superoxide dismutase 1 (SOD1). When researchers removed the gene encoding IP3R2, they found the mice died at more rapid rates, and that there was an increase in inflammation.

“In the blood of sporadic ALS patients, as well as in the models of chronic and acute neurodegeneration, there is a significantly higher expression of intracellular receptor IP3R2,” said co-lead researcher Ludo Van Den Bosch. “When we removed the gene encoding IP3R2, the ALS mice didn’t just die quicker, we also saw systemic inflammation and increased expression of certain cytokines, proteins that plays an important role in the immune system. As a consequence, we conclude that doing the opposite, which is increasing the amount of IP3R2, is a protective response. Not only for ALS, but also for other neurogenerative diseases.”

Initially, researchers believed that by removing IP3R2, it would have a protective effect on the motor neurons affected by the disease. But, the results of the study revealed that the opposite occurred: IP3R2 deletion had a negative effect on the survival of the ALS mouse model.

“The negative effects of IP3R2 removal in other cell types seem to outweigh the potential benefits of removing IP3R2 in motor neurons,” Van Den Bosch said. “In the case of unexpected findings like this, a researcher has 2 options: to stop the project, or to dig deeper into the problem. The last strategy is the most challenging one, as the outcome is uncertain. But, in this case, it has yielded interesting new insights, supported by our data.”

The findings can provide an important foundation and help strengthen the scientific community’s understanding of the mechanism that may protect motor neurons, the authors concluded.

“We have now proven that some aspects of inflammation could play an important role in the disease, which could eventually open new therapeutic options for patients,” Van Den Bosch said. “But if we really want to cure ALS, we need to understand all the ins and outs of ALS on the patient’s cellular level. Studies like ours are crucial pieces of this complex puzzle that we need to solve before we can develop a successful therapy.”

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