Researchers May Have Solved ALS Molecular Misfolding Mystery

Researchers have identified a factor that prevents SOD1 — a protein causing amyotrophic lateral sclerosis (ALS) in a proportion of patients — from misfolding. The finding may advance the development of new drug therapies to stop or slow progression of the disease.

The study, “Endogenous macrophage migration inhibitory factor reduces the accumulation and toxicity of misfolded SOD1 in a mouse model of ALS,” was published in the journal Proceedings of the National Academy of Sciences (PNAS).

Mutations in SOD1 accounts for about 20% of inherited ALS cases, but accumulating evidence suggests that non-mutated, but misfolded versions of the protein might also be involved in sporadic forms of the disease.

“Correct protein folding is critically important, which is why we are focusing on the diverse set of complex cellular mechanisms, including molecular chaperones, that promote efficient folding and prevent toxicity,” Adrian Israelson, PhD and senior author of the study, who heads the Cellular and Molecular Neurodegeneration Lab in the Department of Physiology and Cell Biology at the Ben-Gurion University of the Negev in Israel, said in a news release.

In experiments involving mice and cells grown in the lab, researchers discovered that a molecule known as MIF (migration inhibitory factor) present in macrophage immune cells likely works to prevent SOD1 from misfolding.

MIF belongs to a class of factors, known as chaperones, which help a protein chain to fold into its three-dimensional structure. When the research team cross-bred a mouse with a mutant SOD1 protein, to one lacking MIF, the offspring had a speedier accumulation of SOD1, suggesting that the factor somehow prevented the misfolding of the protein.

SOD1 mutant mice lacking MIF developed disease at a younger age, and had more rapid disease progression. They also died younger than mice with mutant SOD1 who had an intact MIF production.

To test how the reverse scenario would play out, researchers increased the levels of MIF in cells harboring mutant SOD1, grown in the lab. This thwarted the clumping of the protein and prevented cell death.

“This study provides insight into the potential therapeutic role of MIF in suppressing the selective accumulation of misfolded SOD1 in ALS by modulating MIF levels,” said Israelson.