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Updated: Jul 16, 2026
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
BH3-only proteins Bid and Bim(EL) are differentially involved in neuronal dysfunction in mouse models of Huntington's
Juan M García-Martínez1, Esther Pérez-Navarro, Xavier Xifró
1Departament de Biologia Cellular i Anatomia Patològica, Facultat de Medicina, Universitat de Barcelona, IDIBAPS, Barcelona, Spain.
Insights
Huntington's disease (HD) involves increased levels of Bid and Bim(EL) proteins, key regulators of apoptosis. Bid protein levels decrease after mutant huntingtin shutdown, suggesting it may indicate disease progression.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Apoptosis, or programmed cell death, is regulated by Bcl-2 family proteins.
- Neuronal loss in Huntington's disease (HD) may involve apoptosis.
- The role of Bcl-2 family proteins in HD pathogenesis requires further investigation.
Purpose of the Study:
- To investigate the regulation of Bcl-2 family proteins in mouse models of Huntington's disease.
- To determine if changes in these proteins are linked to mutant huntingtin expression.
- To explore the potential reversibility of these changes.
Main Methods:
- Utilized three distinct mouse models of HD expressing exon 1 mutant huntingtin.
- Analyzed protein levels of Bcl-2 family members (Bid, Bim(EL), Bax, Bak, Bad, Bcl-2, Bcl-x(L)) in the striatum.
- Investigated conditional Tet/HD94 mice to assess reversibility after mutant huntingtin shutdown.
Main Results:
- Increased levels of BH3-only proteins Bid and Bim(EL) were observed in the striatum of HD mouse models.
- The increase in Bid and Bim(EL) varied with disease stage and genotype.
- Only Bid protein levels returned to wild-type levels after mutant huntingtin shutdown in Tet/HD94 mice.
Conclusions:
- Enhanced Bid protein levels are an early mechanism associated with continuous mutant huntingtin expression in HD.
- Increased Bid and Bim(EL) may serve as indicators of neuronal dysfunction progression and severity in HD.
- Bid protein level changes offer insights into the dynamic nature of HD pathogenesis.
Abstract:
Apoptosis, a cell death mechanism regulated by Bcl-2 family members, has been proposed as one of the mechanisms leading to neuronal loss in Huntington's disease (HD). Here we examined the regulation of Bcl-2 family proteins in three different mouse models of HD with exon 1 mutant huntingtin: the R6/1, the R6/1:BDNF+/-, and the Tet/HD94 in which the huntingtin transgene is controlled by the tetracycline-inducible system. Our results disclosed an increase in the levels of the BH3-only proteins Bid and Bim(EL) in the striatum of HD mouse models that was different depending on the stage of the disease. At 16 weeks of age, Bid was similarly enhanced in the striatum of R6/1 and R6/1:BDNF+/- mice, whereas Bim(EL) protein levels were enhanced only in R6/1:BDNF+/- mice. In contrast, at later stages of the disease, both genotypes displayed increased levels of Bid and Bim(EL) proteins. Furthermore, Bax, Bak, Bad, Bcl-2, and Bcl-x(L) proteins were not modified in any of the points analyzed. We next explored the potential reversibility of this phenomenon by analyzing conditional Tet/HD94 mice. Constitutive expression of the transgene resulted in increased levels of Bid and Bim(EL) proteins, and only the Bid protein returned to wild-type levels 5 months after mutant huntingtin shutdown. In conclusion, our results show that enhanced Bid protein levels represent an early mechanism linked to the continuous expression of mutant huntingtin that, together with enhanced Bim(EL), may be a reporter of the progress and severity of neuronal dysfunction.
