Related Experiment Video
Updated: Jan 3, 2026
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Discovery of a potent small molecule inhibiting Huntington's disease (HD) pathogenesis via targeting CAG repeats RNA
Eshan Khan1, Subodh Kumar Mishra1, Ribhav Mishra2
1Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, 453552, India.
Insights
Small molecules targeting toxic CAG RNA offer a new therapeutic strategy for neurodegenerative diseases like Huntington's disease (HD) and spinocerebellar ataxias (SCAs). These compounds show promise in cell models by reducing disease-causing RNA toxicity.
Area of Science:
- Neuroscience
- Molecular Biology
- Chemical Biology
Background:
- CAG repeat expansions in RNA are the common cause of fatal neurodegenerative diseases such as Huntington's disease (HD) and spinocerebellar ataxias (SCAs).
- While oligonucleotide therapeutics face challenges in delivery and immune stimulation, small molecules present a promising alternative for targeting these repeat expansion disorders.
- Identifying selective small molecules is crucial for developing effective therapies against polyglutamine (polyQ) mediated diseases.
Purpose of the Study:
- To identify and characterize small molecules that selectively target toxic CAG RNA.
- To investigate the potential of these small molecules as therapeutic agents for neurodegenerative diseases caused by CAG repeat expansions.
Main Methods:
- Utilized a chemical similarity search to discover small molecules targeting toxic CAG RNA.
- Employed biophysical techniques including Circular Dichroism (CD), Isothermal Titration Calorimetry (ITC), and Nuclear Magnetic Resonance (NMR) spectroscopy to assess compound specificity.
- Evaluated the efficacy of lead compounds in HD cell models and patient-derived cells to assess polyQ toxicity alleviation.
Main Results:
- Discovered lead compounds demonstrating specificity for targeting AA mismatches in RNA.
- Biophysical studies confirmed the selective binding of lead compounds to CAG RNA structures.
- Lead compounds effectively reduced polyQ-mediated toxicity in both cellular and patient-derived disease models.
Conclusions:
- The identified small molecules act as effective chemical probes for RNA with AA mismatches.
- These compounds exhibit neuroprotective potential, offering a promising therapeutic avenue for fatal neurodegenerative diseases like HD and SCAs.
- Small molecule-based therapeutics targeting toxic CAG RNA represent a viable strategy for treating repeat expansion disorders.
Abstract:
CAG repeats RNA causes various fatal neurodegenerative diseases exemplified by Huntington's disease (HD) and several spinocerebellar ataxias (SCAs). Although there are differences in the pathogenic mechanisms, these diseases share the common cause, i.e., expansion of CAG repeats. The shared cause of these diseases raises the possibility for the exploiting the common target as a potential therapeutic approach. Oligonucleotide-based therapeutics are designed earlier with the help of the base pairing rule but are not very promiscuous, considering the nonspecific stimulation of the immune system and the poor cellular delivery. Therefore, small molecules-based therapeutics are preferred for targeting the repeats expansion disorders. Here, we have used the chemical similarity search approach to discern the small molecules that selectively target toxic CAG RNA. The lead compounds showed the specificity towards AA mismatch in biophysical studies including CD, ITC, and NMR spectroscopy and thus aided to forestall the polyQ mediated pathogenicity. Furthermore, the lead compounds also explicitly alleviate the polyQ mediated toxicity in HD cell models and patient-derived cells. These findings suggest that the lead compound could act as a chemical probe for AA mismatch containing RNA as well as plays a neuroprotective role in fatal neurodegenerative diseases like HD and SCAs.
More Related Videos
Related Concept Videos
02:15Experimental RNAi
02:30siRNA - Small Interfering RNAs
In the cytoplasm, siRNA is processed from a double-stranded RNA, which comes from either endogenous DNA transcription or exogenous sources like a virus. This double-stranded RNA is then cleaved by the...
01:23RNA Interference
This process occurs naturally in cells, often through the activity of genomically-encoded microRNAs. Researchers can take advantage of this mechanism by introducing synthetic RNAs to deactivate specific genes for research or therapeutic purposes. For example, RNAi could be used...