ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2012
Caspase-6 activity in a BACHD mouse modulates steady-state levels of mutant huntingtin protein but is not necessary for production of a 586 amino acid proteolytic fragment.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 49 citations in OpenAlex.
- In vivo CRISPR base editing for treatment of Huntington's disease.Nature biomedical engineering · 2026Article
- Truncation of mutant huntingtin in knock-in mice demonstrates exon1 huntingtin is a key pathogenic form.Nature communications · 2020Article
- Targeting the proteostasis network in Huntington's disease.Ageing research reviews · 2019Review
- Differential susceptibility of striatal, hippocampal and cortical neurons to Caspase-6.Cell death and differentiation · 2018Article
- Salivary levels of total huntingtin are elevated in Huntington's disease patients.Scientific reports · 2018Article
- Preventing mutant huntingtin proteolysis and intermittent fasting promote autophagy in models of Huntington disease.Acta neuropathologica communications · 2018Article
- Caspase-6 mediates resistance against Burkholderia pseudomallei infection and influences the expression of detrimental cytokines.PloS one · 2017Article
- Huntingtin proteolysis releases non-polyQ fragments that cause toxicity through dynamin 1 dysregulation.The EMBO journal · 2015Article
- Integration-independent Transgenic Huntington Disease Fragment Mouse Models Reveal Distinct Phenotypes and Life Span in Vivo.The Journal of biological chemistry · 2015Article
- Proteolytic cleavage of ataxin-7 promotes SCA7 retinal degeneration and neurological dysfunction.Human molecular genetics · 2015Article
- A Huntingtin-based peptide inhibitor of caspase-6 provides protection from mutant Huntingtin-induced motor and behavioral deficits.Human molecular genetics · 2015Article
- Transgenic animal models for study of the pathogenesis of Huntington's disease and therapy.Drug design, development and therapy · 2015Review
- Novel BAC Mouse Model of Huntington's Disease with 225 CAG Repeats Exhibits an Early Widespread and Stable Degenerative Phenotype.Journal of Huntington's disease · 2015Article
- Identification of a post-translationally myristoylated autophagy-inducing domain released by caspase cleavage of huntingtin.Human molecular genetics · 2014Article
- From pathways to targets: understanding the mechanisms behind polyglutamine disease.BioMed research international · 2014Review
- Cerebrospinal fluid tau cleaved by caspase-6 reflects brain levels and cognition in aging and Alzheimer disease.Journal of neuropathology and experimental neurology · 2013Article
- Genetic manipulations of mutant huntingtin in mice: new insights into Huntington's disease pathogenesis.The FEBS journal · 2013Review
- PolyQ disease: misfiring of a developmental cell death program?Trends in cell biology · 2013Review
- Caspase-6 does not contribute to the proteolysis of mutant huntingtin in the HdhQ150 knock-in mouse model of Huntington's disease.PLoS currents · 2012Article
Corrections and comments
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Authors and funding
18 authors at 5 institutions in 2 countries.
Funding
Abstract
Huntington's disease (HD) is caused by a mutation in the huntingtin (htt) gene encoding an expansion of glutamine repeats at the N terminus of the Htt protein. Proteolysis of Htt has been identified as a critical pathological event in HD models. In particular, it has been postulated that proteolysis of Htt at the putative caspase-6 cleavage site (at amino acid Asp-586) plays a critical role in disease progression and pathogenesis. However, whether caspase-6 is indeed the essential enzyme that cleaves Htt at this site in vivo has not been determined. To evaluate, we crossed the BACHD mouse model with a caspase-6 knock-out mouse (Casp6(-/-)). Western blot and immunocytochemistry confirmed the lack of caspase-6 protein in Casp6(-/-) mice, regardless of HD genotype. We predicted the Casp6(-/-) mouse would have reduced levels of caspase-6 Htt fragments and increased levels of full-length Htt protein. In contrast, we found a significant reduction of full-length mutant Htt (mHtt) and fragments in the striatum of BACHD Casp6(-/-) mice. Importantly, we detected the presence of Htt fragments consistent with cleavage at amino acid Asp-586 of Htt in the BACHD Casp6(-/-) mouse, indicating that caspase-6 activity cannot fully account for the generation of the Htt 586 fragment in vivo. Our data are not consistent with the hypothesis that caspase-6 activity is critical in generating a potentially toxic 586 aa Htt fragment in vivo. However, our studies do suggest a role for caspase-6 activity in clearance pathways for mHtt protein.
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