Researchers Find ‘Harmful’ ALS Factor Actually Protects Neurons from Inflammation

Attempting to lower a specific protein that is higher in patients with amyotrophic lateral sclerosis (ALS), researchers discovered that the protein does not contribute to the disease as believed. Instead, it protects neurons from rampaging inflammation.

The findings, published in the journal Human Molecular Genetics under the title “Genetic ablation of IP3 receptor 2 increases cytokines and decreases survival of SOD1G93A mice,” not only advanced understanding of ALS, but also gives researchers insights into other neurological diseases such as multiple sclerosis or stroke.

Professor Ludo Van Den Bosch at VIB — Flanders Interuniversity Institute for Biotechnology — and the University of Leuven, led the research team exploring mice with a mutation in the SOD1 gene, the most common mutation that leads to ALS in humans.

Earlier research showed that in patients with sporadic ALS, and in mouse models of both chronic and acute neurodegeneration including ALS, the protein IP3R2 is found at high levels in the blood. IP3R2 is a receptor normally found inside cells.

The research team previously demonstrated that increasing the factor in neurons had a negative impact on the disease in ALS mice, so they figured that preventing the increase in the levels of IP3R2 could slow or halt the disease.  They were surprised by what they found.

Removal of the factor in mice made the condition worse; mice died more quickly and signs of inflammation peaked. Researchers also noted that the removal of IP3R2 increased the levels of immune signaling molecules IFNγ, IL-6, and IL1α, representing an activation of the innate immune system.

The findings indicate that IP3R2 might be a protective factor.

“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 a news release.

“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. 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,” he said.