Study identifies gene that could lead to new ALS therapies

Written by Peter Brown

Researchers from the Ben-Gurion University of the Negev (Beersheba, Israel) have identified a gene that is able to inhibit the accumulation of misfolded superoxide dismutase (SOD1) proteins in in vivo amyotrophic lateral sclerosis (ALS) mouse models. The researchers hope that their observations could lead to the development of new therapies for ALS.
The study, recently published in PNAS, demonstrated that modulating levels of endogenous macrophage migration inhibitory factor (MIF) may provide a possible therapeutic treatment of suppressing SOD1 in ALS. Approximately 10% of ALS cases are genetically inherited, of which 20% of cases are a result of mutations in the SOD1 gene: these mutations  lead to the accumulation of misfolded SOD1 proteins that provoke the death of motor neurons.

“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,” commented Adrian Israelson (Ben-Gurion University).

The team was able to determine that the MIF gene, which regulates cell inflammation and immunity, acts as a chaperone for misfolded SOD1 proteins in vivo. They observed that eliminating MIF in mutant SOD1 mouse models of familial ALS led to enhanced accumulation of misfolded protein, accelerated disease onset and late disease progression, and shortened lifespan.

“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,” concluded Israelson.

The findings of this study suggest that MIF plays a significant role in the folding and misfolding of SOD1 in vivo, proposing a role for up-regulating MIF within the CNS to modulate the selective accumulation of misfolded SOD1.

Sources: Layton-Jaimes MF, Benaim C, Abu-Hamad S et al. Endogenous macrophage migration inhibitory factor reduces the accumulation and toxicity of misfolded SOD1 in a mouse model of ALS. PNAS 113(36) 10198–10203 (2016); https://aabgu.org/gene-modulation-for-als-treatment/