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Updated: May 27, 2026
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Genetic ablation and chemical inhibition of IP3R1 reduce mutant huntingtin aggregation
Peter O Bauer1, Roman Hudec, Shoichiro Ozaki
1Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Insights
Inhibiting inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) reduces Huntington's disease (HD) protein aggregation. This study confirms IP3R1
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Huntington's disease (HD) is a neurodegenerative disorder linked to expanded polyglutamine (polyQ) in huntingtin (htt).
- Inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) inhibition previously showed potential in reducing pathogenic protein aggregation.
- Concerns exist regarding the specificity and toxicity of current IP3R1 inhibitors like 2-aminoethyl diphenylborinate (2-APB).
Purpose of the Study:
- To establish a direct link between IP3R1 and polyQ aggregation in Huntington's disease.
- To investigate novel, less toxic, and more specific IP3R1 inhibitors for potential therapeutic applications in HD.
- To explore the mechanisms underlying the anti-aggregation effects of IP3R1-targeting compounds.
Main Methods:
- Down-regulation of IP3R1 levels using short hairpin RNA (shRNA).
- Testing of 2-aminoethyl diphenylborinate (2-APB) analogs for their effects on mutant huntingtin (htt) aggregation.
- Assessing the correlation between analog efficacy and inhibition of IP3-induced Ca(2+) release (IICR) and store-operated Ca(2+) entry (SOCE).
Main Results:
- Down-regulation of IP3R1 levels significantly reduced mutant htt aggregation.
- The anti-aggregation effects of 2-APB analogs showed a weak correlation with IP3R1 inhibition (IICR).
- No correlation was observed between analog efficacy and inhibition of store-operated Ca(2+) entry (SOCE).
Conclusions:
- IP3R1 plays a direct role in modulating mutant huntingtin aggregation.
- While IP3R1 inhibition contributes to the anti-aggregation effect, other mechanisms are also involved in the action of 2-APB related compounds.
- Findings pave the way for developing more targeted therapies for Huntington's disease by exploring novel compounds and pathways.
Abstract:
Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by an expansion of the polyglutamine (polyQ) stretch in huntingtin (htt). Previously, it has been shown that inhibition of the inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) activity reduced aggregation of pathogenic polyQ proteins. Experimentally, this effect was achieved by modification of the intracellular IP3 levels or by application of IP3R1 inhibitors, such as 2-aminoethyl diphenylborinate (2-APB). Unfortunately, there are certain concerns about the 2-APB specificity and cytotoxicity. Moreover, a direct link between IP3R1 and polyQ aggregation has not been shown yet. In this study we show, that down-regulation of the IP3R1 levels by shRNA reduced the aggregation of mutant htt. We tested 2-APB analogs in an attempt to identify less toxic and more IP3R1-specific compounds and found that the effect of these analogs on the reduction of the mutant htt aggregation did weakly correlate with their inhibitory action toward the IP3-induced Ca(2+) release (IICR). Their effect on aggregation was not correlated with the store-operated Ca(2+) entry (SOCE), which is another target of the 2-APB related compounds. Our findings suggest that besides functional contribution of the IP3R inhibition on the mutant htt aggregation there are additional mechanisms for the anti-aggregation effect of the 2-APB related compounds.
