By Michelle Jaffee
A new study shows that the diabetes drug metformin improved motor skills and decreased neuroinflammation in a mouse model of spinocerebellar ataxia type 8, a debilitating neurological disorder.
Known as SCA8, it is among 70 neurological diseases caused by repeat expansion mutations, in which specific DNA sequences are repeated hundreds to thousands of extra times. Symptoms of SCA8 include difficulty walking and slurred speech, and it has no effective treatments.
In the journal Life Science Alliance, Laura Ranum, Ph.D., and Lisa Romano, Ph.D., report that metformin — a widely available, FDA-approved drug — holds promise for treating SCA8 and many other conditions.
Ranum’s UF research team moved to test metformin, a type 2 diabetes drug, in SCA8 after previously demonstrating that it could improve disease features in another repeat expansion mouse model — a genetic form of ALS caused by a repeat expansion in the C9orf72 gene.
The team found that at the molecular level, metformin lowered levels of toxic proteins called repeat associated non-AUG (RAN) proteins, which are known to accumulate and contribute to SCA8. Functionally, metformin improved coordination and the ability of mice to move, the researchers reported.
“While this study was done in a mouse model of SCA8 and further study needs to be done to see if this will be effective in human patients, we are excited because the results are similar to a previous study done in C9orf72 ALS mice, another RAN protein disease,” said Ranum, director of UF’s Center for NeuroGenetics.
Ranum noted there is potential for several other diseases as well: A total of 18 repeat expansion diseases are known to produce similar toxic proteins.
Thus these preclinical results provide a foundation not only to test metformin in human clinical trials for SCA8 but also to test if metformin can reduce RAN proteins and improve disease in other repeat expansion disorders.
In the SCA8 study, “the animals treated with metformin showed behavioral changes that rescued them back to a non-transgenic level, meaning they were basically similar to the healthy animal,” said Romano, a research assistant professor in Ranum’s lab.
“We think using metformin results in combinational benefits, with a reduction of both toxic RAN proteins and decreased neuroinflammation, which is an important factor in neurodegenerative disease,” she said.