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Loss of Hap1 selectively promotes striatal degeneration in Huntington disease mice
Qiong Liu1,2,3, Siying Cheng1,2, Huiming Yang2
1Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China.
Insights
Depleting Hap1 in Huntington disease (HD) mice caused striatal neuron loss, requiring mutant huntingtin (HTT). This suggests Hap1 and Rhes contribute to selective neurodegeneration in HD.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington disease (HD) is characterized by selective neurodegeneration in the striatum.
- This neurodegeneration is linked to expanded polyglutamine (polyQ) repeats in the huntingtin (HTT) protein.
Purpose of the Study:
- To investigate the role of Hap1 (huntingtin-associated protein 1) in selective neurodegeneration in HD.
- To explore the interaction between Hap1, mutant HTT, and Rhes in HD pathogenesis.
Main Methods:
- Adeno-associated virus (AAV) mediated depletion of Hap1 in adult HD knock-in (KI) mouse brains.
- Analysis of neuronal loss in the striatum.
- Investigation of Rhes binding to N-terminal HTT and HTT sumoylation.
Main Results:
- AAV-mediated Hap1 depletion in HD KI mice resulted in selective striatal neuronal loss.
- This neuronal loss was dependent on the presence of mutant HTT.
- Hap1 deficiency led to increased binding of Rhes to N-terminal HTT and enhanced HTT sumoylation.
Conclusions:
- Hap1 plays a crucial role in protecting striatal neurons in the context of HD.
- The interplay between Hap1, Rhes, and mutant HTT contributes to selective neurodegeneration in HD.
- Multiple factors, including cellular stress, are involved in the complex mechanisms of HD neurodegeneration.
Abstract:
Huntington disease (HD) is an ideal model for investigating selective neurodegeneration, as expanded polyQ repeats in the ubiquitously expressed huntingtin (HTT) cause the preferential neurodegeneration in the striatum of the HD patient brains. Here we report that adeno-associated virus (AAV) transduction-mediated depletion of Hap1, the first identified huntingtin-associated protein, in adult HD knock-in (KI) mouse brains leads to selective neuronal loss in the striatum. Further, Hap1 depletion-mediated neuronal loss via AAV transduction requires the presence of mutant HTT. Rhes, a GTPase that is enriched in the striatum and sumoylates mutant HTT to mediate neurotoxicity, binds more N-terminal HTT when Hap1 is deficient. Consistently, more soluble and sumoylated N-terminal HTT is presented in HD KI mouse striatum when HAP1 is absent. Our findings suggest that both Rhes and Hap1 as well as cellular stress contribute to the preferential neurodegeneration in HD, highlighting the involvement of multiple factors in selective neurodegeneration.
