ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2010
Cleavage at the 586 amino acid caspase-6 site in mutant huntingtin influences caspase-6 activation in vivo.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 106 citations in OpenAlex.
- The Intricate Role of Caspase-6 and Death Receptor-6 in Neurodegenerative Diseases.Cell biochemistry and biophysics · 2026Review
- In silico discovery of natural compound-derived multi-target inhibitor for Huntington's disease therapy.Scientific reports · 2026Article
- Oxidative/Nitrosative Stress, Apoptosis, and Redox Signaling: Key Players in Neurodegenerative Diseases.Journal of biochemical and molecular toxicology · 2025Review
- Protective Proteolysis in Huntington's Disease: Unraveling the Role of Post-Translational Myristoylation of Huntingtin in Autophagy.Journal of Huntington's disease · 2024Review
- A Review on Caspases: Key Regulators of Biological Activities and Apoptosis.Molecular neurobiology · 2023Review
- Coaggregation of polyglutamine (polyQ) proteins is mediated by polyQ-tract interactions and impairs cellular proteostasis.Acta biochimica et biophysica Sinica · 2023Article
- A pathogenic proteolysis-resistant huntingtin isoform induced by an antisense oligonucleotide maintains huntingtin function.JCI insight · 2022Article
- Non-Canonical Roles of Apoptotic Caspases in the Nervous System.Frontiers in cell and developmental biology · 2022Review
- PolyQ-expanded proteins impair cellular proteostasis of ataxin-3 through sequestering the co-chaperone HSJ1 into aggregates.Scientific reports · 2021Article
- Conformational transitions of caspase-6 in substrate-induced activation process explored by perturbation-response scanning combined with targeted molecular dynamics.Computational and structural biotechnology journal · 2021Article
- Newly Identified Function of Caspase-6 in ZBP1-mediated Innate Immune Responses, NLRP3 Inflammasome Activation, PANoptosis, and Host Defense.Journal of cellular immunology · 2020Article
- Site-specific phosphorylation and caspase cleavage of GFAP are new markers of Alexander disease severity.eLife · 2019Article
- The Role of Neuronal NLRP1 Inflammasome in Alzheimer's Disease: Bringing Neurons into the Neuroinflammation Game.Molecular neurobiology · 2019Review
- Activation of Caspase-6 Is Promoted by a Mutant Huntingtin Fragment and Blocked by an Allosteric Inhibitor Compound.Cell chemical biology · 2019Article
- Tri-arginine exosite patch of caspase-6 recruits substrates for hydrolysis.The Journal of biological chemistry · 2019Article
- Targeting the proteostasis network in Huntington's disease.Ageing research reviews · 2019Review
- Brainiac Caspases: Beyond the Wall of Apoptosis.Frontiers in cellular neuroscience · 2019Review
- Therapeutic approaches to Huntington disease: from the bench to the clinic.Nature reviews. Drug discovery · 2018Review
- Differential susceptibility of striatal, hippocampal and cortical neurons to Caspase-6.Cell death and differentiation · 2018Article
- Preventing mutant huntingtin proteolysis and intermittent fasting promote autophagy in models of Huntington disease.Acta neuropathologica communications · 2018Article
Corrections and comments
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Authors and funding
14 authors at 5 institutions in 3 countries.
Funding
Abstract
Caspase cleavage of huntingtin (htt) and nuclear htt accumulation represent early neuropathological changes in brains of patients with Huntington's disease (HD). However, the relationship between caspase cleavage of htt and caspase activation patterns in the pathogenesis of HD remains poorly understood. The lack of a phenotype in YAC mice expressing caspase-6-resistant (C6R) mutant htt (mhtt) highlights proteolysis of htt at the 586 aa caspase-6 (casp6) site as a key mechanism in the pathology of HD. The goal of this study was to investigate how proteolysis of htt at residue 586 plays a role in the pathogenesis of HD and determine whether inhibiting casp6 cleavage of mhtt alters cell-death pathways in vivo. Here we demonstrate that activation of casp6, and not caspase-3, is observed before onset of motor abnormalities in human and murine HD brain. Active casp6 levels correlate directly with CAG size and inversely with age of onset. In contrast, in vivo expression of C6R mhtt attenuates caspase activation. Increased casp6 activity and apoptotic cell death is evident in primary striatal neurons expressing caspase-cleavable, but not C6R, mhtt after NMDA application. Pretreatment with a casp6 inhibitor rescues the apoptotic cell death observed in this paradigm. These data demonstrate that activation of casp6 is an early marker of disease in HD. Furthermore, these data provide a clear link between excitotoxic pathways and proteolysis and suggest that C6R mhtt protects against neurodegeneration by influencing the activation of neuronal cell-death and excitotoxic pathways operative in HD.
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