Related Experiment Video
Updated: May 19, 2026
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Methylene blue modulates huntingtin aggregation intermediates and is protective in Huntington's disease models
Emily Mitchell Sontag1, Gregor P Lotz, Namita Agrawal
1Department of Biological Chemistry, Psychiatry and Human Behavior, University of California, Irvine, California 92697, USA.
Insights
Methylene blue (MB) shows therapeutic potential for Huntington's disease (HD) by inhibiting mutant Huntingtin (Htt) protein aggregation and reducing neurotoxicity in preclinical models. MB also increased brain-derived neurotrophic factor (BDNF) levels, suggesting a disease-modifying effect.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Huntington's disease (HD) is a fatal neurodegenerative disorder caused by expanded CAG trinucleotide repeats in the Huntingtin (Htt) gene.
- Mutant Htt protein forms aggregates, leading to cellular dysfunction and neurodegeneration.
- Current treatments for HD are limited to symptom management, lacking disease-modifying effects.
Purpose of the Study:
- To investigate the therapeutic potential of methylene blue (MB) in Huntington's disease.
- To determine if MB can inhibit mutant Htt aggregation and reduce associated neurotoxicity.
Main Methods:
- In vitro studies using recombinant proteins to assess MB's effect on aggregation.
- Cellular assays to evaluate MB's impact on mutant Htt accumulation and neurotoxicity.
- In vivo studies using Drosophila melanogaster and R6/2 mouse models of HD to assess MB's efficacy and effects on BDNF.
Main Results:
- MB inhibited aggregation of recombinant mutant Htt protein, including preformed oligomers and fibrils.
- MB reduced the accumulation of insoluble mutant Htt in cells and decreased oligomer size and number.
- MB treatment improved neuronal survival, reduced neurodegeneration and aggregation in HD models, and increased BDNF levels in vivo.
Conclusions:
- Methylene blue demonstrates significant therapeutic potential for Huntington's disease by targeting mutant Htt aggregation and neurotoxicity.
- MB's ability to modulate protein aggregation and enhance neurotrophic factors suggests a promising disease-modifying strategy.
- MB is a well-tolerated compound with potential for clinical application in treating Huntington's disease.
Abstract:
Huntington's disease (HD) is a devastating neurodegenerative disorder with no disease-modifying treatments available. The disease is caused by expansion of a CAG trinucleotide repeat and manifests with progressive motor abnormalities, psychiatric symptoms, and cognitive decline. Expression of an expanded polyglutamine repeat within the Huntingtin (Htt) protein impacts numerous cellular processes, including protein folding and clearance. A hallmark of the disease is the progressive formation of inclusions that represent the culmination of a complex aggregation process. Methylene blue (MB), has been shown to modulate aggregation of amyloidogenic disease proteins. We investigated whether MB could impact mutant Htt-mediated aggregation and neurotoxicity. MB inhibited recombinant protein aggregation in vitro, even when added to preformed oligomers and fibrils. MB also decreased oligomer number and size and decreased accumulation of insoluble mutant Htt in cells. In functional assays, MB increased survival of primary cortical neurons transduced with mutant Htt, reduced neurodegeneration and aggregation in a Drosophila melanogaster model of HD, and reduced disease phenotypes in R6/2 HD modeled mice. Furthermore, MB treatment also promoted an increase in levels of BDNF RNA and protein in vivo. Thus, MB, which is well tolerated and used in humans, has therapeutic potential for HD.
