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Updated: Jun 22, 2026
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
HAP40 modulates mutant Huntingtin aggregation and toxicity in Huntington's disease mice
Laiqiang Chen1,2, Yiyang Qin1,2, Tingting Guo1
1Guangdong Key Laboratory of Non-human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.
Insights
Huntingtin-associated protein 40 (HAP40) regulates Huntingtin (HTT) protein levels in Huntington's disease (HD). Lowering HAP40 worsens HD symptoms, while increasing it offers therapeutic benefits.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington's disease (HD) is a monogenic neurodegenerative disorder.
- It stems from a CAG trinucleotide repeat expansion in the Huntingtin (HTT) gene.
- Huntingtin-associated protein 40 (HAP40) binds HTT and maintains its conformation in vitro.
Purpose of the Study:
- To investigate the role of HAP40 in Huntington's disease pathogenesis.
- To explore HAP40 as a potential therapeutic target for HD.
Main Methods:
- Studied HAP40 expression levels in mouse models of HD.
- Manipulated HAP40 levels in the striatum of HD140Q knock-in (KI) mice.
- Assessed mutant HTT aggregation, neuronal loss, and behavioral deficits.
- Investigated the mechanism of HAP40 interaction with mutant HTT.
Main Results:
- HAP40 expression inversely correlates with mutant HTT aggregates in mouse brains.
- HAP40 depletion in HD mice enhanced mutant HTT aggregation and neuronal loss.
- HAP40 overexpression reduced mutant HTT aggregation and improved behavioral deficits.
- HAP40 preferentially binds mutant HTT and promotes its Lys48-linked ubiquitination.
Conclusions:
- HAP40 is a key regulator of HTT protein homeostasis in vivo.
- HAP40 plays a protective role in Huntington's disease.
- HAP40 represents a promising therapeutic target for HD treatment.
Abstract:
Huntington's disease (HD) is a monogenic neurodegenerative disease, caused by the CAG trinucleotide repeat expansion in exon 1 of the Huntingtin (HTT) gene. The HTT gene encodes a large protein known to interact with many proteins. Huntingtin-associated protein 40 (HAP40) is one that shows high binding affinity with HTT and functions to maintain HTT conformation in vitro. However, the potential role of HAP40 in HD pathogenesis remains unknown. In this study, we found that the expression level of HAP40 is in parallel with HTT but inversely correlates with mutant HTT aggregates in mouse brains. Depletion of endogenous HAP40 in the striatum of HD140Q knock-in (KI) mice leads to enhanced mutant HTT aggregation and neuronal loss. Consistently, overexpression of HAP40 in the striatum of HD140Q KI mice reduced mutant HTT aggregation and ameliorated the behavioral deficits. Mechanistically, HAP40 preferentially binds to mutant HTT and promotes Lysine 48-linked ubiquitination of mutant HTT. Our results revealed that HAP40 is an important regulator of HTT protein homeostasis in vivo and hinted at HAP40 as a therapeutic target in HD treatment.
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