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PROTAC-Mediated Degradation of mHTT Aggregates Attenuates Neurotoxicity in Cellular and R6/2 Mouse Models of
Po-Chao Lu1,2,3, Yung-An Huang1, Niaz Wali1
1Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan.
Insights
Researchers developed novel PROTACs to selectively degrade aggregated mutant huntingtin (mHTT) in Huntington's disease (HD). This approach successfully reduced mHTT, improved symptoms in a mouse model, and shows promise for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Huntington's disease (HD) is a fatal neurodegenerative disorder caused by expanded CAG repeats in the HTT gene, leading to mutant huntingtin (mHTT) aggregation and neuronal death.
- Current therapeutic strategies for HD, such as HTT-lowering approaches, face limitations including invasive delivery methods and non-specific suppression of both wild-type and mutant huntingtin.
- Selective degradation of aggregated mHTT offers a potential disease-modifying therapeutic strategy for HD.
Purpose of the Study:
- To develop and synthesize proteolysis-targeting chimeras (PROTACs) capable of selectively degrading aggregated mutant huntingtin (mHTT).
- To evaluate the efficacy and safety of the lead PROTAC compound (PROTAC 2') in cellular and animal models of Huntington's disease.
- To assess the potential of aggregate-selective degradation as a therapeutic approach for Huntington's disease and other neurodegenerative proteinopathies.
Main Methods:
- Synthesis of PROTACs, with the lead compound (PROTAC 2') featuring an aggregate-binding ligand linked to pomalidomide (a cereblon E3 ligase recruiter).
- Assessment of PROTAC 2's selectivity for degrading aggregated mHTT versus wild-type huntingtin in cell models.
- Evaluation of PROTAC 2's ability to reduce mHTT-induced cytotoxicity, penetrate the blood-brain barrier (BBB), and improve motor function and survival in an R6/2 HD mouse model.
Main Results:
- PROTAC 2' selectively degraded aggregated mHTT without affecting wild-type huntingtin, significantly reducing mHTT-induced cytotoxicity in cell models.
- LC-MS/MS analysis confirmed that PROTAC 2' can penetrate the blood-brain barrier after subcutaneous administration.
- In the R6/2 HD mouse model, PROTAC 2' delivery improved body weight, motor coordination, and survival, accompanied by reduced mHTT aggregation and neuroinflammation.
Conclusions:
- Aggregate-selective degradation using PROTACs represents a promising therapeutic strategy for Huntington's disease, offering an alternative to conventional HTT-lowering methods.
- PROTAC 2' demonstrates therapeutic potential by selectively degrading mHTT aggregates and ameliorating disease phenotypes in a preclinical HD model.
- This study supports the broader application of PROTAC-based therapeutics for treating neurodegenerative proteinopathies characterized by protein aggregation.
Abstract:
Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene, producing mutant huntingtin (mHTT) that misfolds into β-sheet-rich aggregates and drives neuronal loss. Current HTT-lowering strategies face challenges, including invasive delivery and nonselective suppression of wild-type HTT. Here, we report the development and synthesis of proteolysis-targeting chimeras (PROTACs) to selectively degrade aggregated mHTT. The lead compound, PROTAC 2', consists of a (pyridylvinyl)aniline aggregate-binding ligand linked via polyethylene glycol spacers to pomalidomide, an E3 ligase recruiter for cereblon. PROTAC 2' selectively degraded mHTT aggregates without affecting wild-type huntingtin and significantly reduced mHTT-induced cytotoxicity in the cell model. LC-MS/MS analysis confirmed the blood-brain barrier (BBB) penetration ability of PROTAC 2' following subcutaneous administration. In an R6/2 HD mouse model, continuous PROTAC 2' delivery via osmotic pumps improved body weight, motor coordination, and survival, correlating with reduced mHTT aggregation and neuroinflammation in the brain. These results highlight the therapeutic potential of aggregate-selective degradation as a disease-modifying strategy for HD, providing a promising alternative to conventional HTT-lowering approaches and supporting the broader potential of PROTAC-based therapeutics for neurodegenerative proteinopathies.
