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Updated: Jul 14, 2026
07:08
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Loss of huntingtin function complemented by small molecules acting as repressor element 1/neuron restrictive silencer
Dorotea Rigamonti1, Daniele Bolognini, Cesare Mutti
1Centre for Stem Cell Research and Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, Milan 20133, Italy.
The Journal of Biological Chemistry
|June 15, 2007
Summary
Researchers identified compounds that restore neuronal gene expression, including brain-derived neurotrophic factor (BDNF), in Huntington disease (HD) cells. This offers a potential therapeutic strategy for HD and other neurodegenerative disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Huntington disease (HD) is linked to increased repressor element 1/neuron restrictive silencer element (RE1/NRSE) silencing activity.
- This activity reduces the transcription of crucial neuronal genes like brain-derived neurotrophic factor (BDNF), contributing to neuronal vulnerability in HD.
Purpose of the Study:
- To develop a cell-based assay for monitoring RE1/NRSE silencing activity.
- To identify compounds that can counteract RE1/NRSE-mediated gene silencing.
- To explore therapeutic strategies for Huntington disease by restoring neuronal gene expression.
Main Methods:
- Developed and validated a cell-based reporter assay for RE1/NRSE silencing activity.
- Validated the assay using genetic inactivation and pharmacological stimulation of transcription.
- Conducted a pilot compound screen to identify potential therapeutic agents.
Main Results:
- Identified three structurally related compounds that up-regulate reporter expression at low nanomolar concentrations.
- Demonstrated that these compounds effectively increase endogenous BDNF levels in HD cells.
- Showed that one compound significantly improves the viability of HD cells.
Conclusions:
- The developed reporter assay is a valuable tool for studying RE1/NRSE activity.
- Identified compounds represent a promising new avenue for developing drugs targeting HD and other neurodegenerative diseases.
- Pharmacological upregulation of BDNF and other RE1/NRSE-regulated genes offers a potential therapeutic approach.
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