Related Experiment Video
Updated: Mar 30, 2026
Strategies for Assessing Autistic-Like Behaviors in Mice
Published on: September 20, 2024
Metformin improves RAN protein pathology, alternative splicing, and behavioral phenotypes in SCA8 mice
Lisa El Romano1,2, Setsuki Tsukagoshi1,2, Emily E Davey-Osuch1,2
1Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL, USA.
Abstract:
Spinocerebellar ataxia type 8 (SCA8) is a member of a group of dominantly inherited, debilitating neurological diseases caused by CAG•CTG expansions for which there are no effective treatments. RAN translation, which was discovered in SCA8, has previously been shown to occur across CAG and CUG expansion transcripts, making treatments for SCA8 potentially relevant to a broad group of diseases, including SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, Huntington's disease, and myotonic dystrophy type 1. In addition, CUG and CAG expansion transcripts have been reported to cause RNA gain-of-function effects. Using SCA8 BAC transgenic mice as a model for CAG•CTG expansion diseases, we now show that metformin improves ambulatory performance using rotarod, DigiGait, and open-field testing. At the molecular level, metformin-treated mice show reduced RAN protein levels and improved splicing, without altering sense or antisense RNA levels. Metformin-treated mice also show decreased neuroinflammation, with reduced astrogliosis and fewer activated microglia. These data provide strong preclinical support for testing metformin in clinical trials for SCA8 and potentially the broader group of CAG•CTG repeat expansion disorders.
Insights
Metformin shows promise for treating spinocerebellar ataxia type 8 (SCA8) and related repeat expansion disorders. This study found metformin improved motor function and reduced toxic protein production in a mouse model, suggesting potential for clinical trials.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Spinocerebellar ataxia type 8 (SCA8) is a debilitating neurological disease caused by CAG•CTG repeat expansions.
- Current treatments for SCA8 and related disorders are lacking.
- RAN translation and RNA gain-of-function effects are implicated in these diseases.
Purpose of the Study:
- To investigate the therapeutic potential of metformin in a mouse model of SCA8.
- To evaluate metformin's effects on motor function, RAN translation, RNA splicing, and neuroinflammation.
Main Methods:
- Utilized SCA8 BAC transgenic mice as a disease model.
- Assessed ambulatory performance using rotarod, DigiGait, and open-field tests.
- Analyzed molecular changes including RAN protein levels, RNA splicing, and neuroinflammation markers.
Main Results:
- Metformin significantly improved motor performance in SCA8 mice.
- Metformin treatment reduced RAN protein levels and corrected RNA splicing.
- Reduced neuroinflammation, including astrogliosis and microglial activation, was observed in metformin-treated mice.
Conclusions:
- Metformin demonstrates significant preclinical efficacy for SCA8.
- These findings support further investigation of metformin in clinical trials for SCA8.
- Metformin may offer a therapeutic strategy for a broader range of CAG•CTG repeat expansion disorders.
