ArticleProceedings of the National Academy of Sciences of the United States of America2019
IKKβ slows Huntington's disease progression in R6/1 mice.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 1 of them a synthesis that pooled it.
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Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it, 36 citations in OpenAlex.
- Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)Autophagy · 2021Guideline
- Huntingtin knockdown dysregulates autophagic degradation of Apolipoprotein E.Journal of Huntington's disease · 2026Article
- Post-Translational Modifications of Huntingtin: Mechanistic Insights and Therapeutic Opportunities in Huntington's Disease.International journal of molecular sciences · 2025Review
- Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery.Signal transduction and targeted therapy · 2025Review
- Regulation of Mutant Huntingtin Mitochondrial Toxicity by Phosphomimetic Mutations within Its N-Terminal Region.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Ubiquitin specific peptidase 11 knockdown slows Huntington's disease progression via regulating mitochondrial dysfunction and neuronal damage depending on PTEN-mediated AKT pathway.Molecular medicine (Cambridge, Mass.) · 2025Article
- Huntingtin contains an ubiquitin-binding domain and regulates lysosomal targeting of mitochondrial and RNA-binding proteins.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Protein modification in neurodegenerative diseases.MedComm · 2024Review
- IκB kinase phosphorylates cytoplasmic TDP-43 and promotes its proteasome degradation.The Journal of cell biology · 2024Article
- Gut Microbiota as a Modifier of Huntington's Disease Pathogenesis.Journal of Huntington's disease · 2024Review
- Review
- IKBKB reduces huntingtin aggregation by phosphorylating serine 13 via a non-canonical IKK pathway.Life science alliance · 2023Article
- Ependyma in Neurodegenerative Diseases, Radiation-Induced Brain Injury and as a Therapeutic Target for Neurotrophic Factors.Biomolecules · 2023Review
- Dual Antioxidant DH-217 Mitigated Cerebral Ischemia-Reperfusion Injury by Targeting IKKβ/Nrf2/HO-1 Signal Axis.Neurochemical research · 2023Article
- Protein Kinase CK2 and Its Potential Role as a Therapeutic Target in Huntington's Disease.Biomedicines · 2022Review
- IKKβ Alleviates Neuron Injury in Alzheimer's Disease via Regulating Autophagy and RIPK1-Mediated Necroptosis.Molecular neurobiology · 2022Article
- IKKβ signaling mediates metabolic changes in the hypothalamus of a Huntington disease mouse model.iScience · 2022Article
- Cooperation of cell adhesion and autophagy in the brain: Functional roles in development and neurodegenerative disease.Matrix biology plus · 2021Review
- Effects of mutant huntingtin inactivation on Huntington disease-related behaviours in the BACHD mouse model.Neuropathology and applied neurobiology · 2021Article
- Article
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Authors and funding
15 authors at 2 institutions in 1 country.
Funding
Abstract
Neuroinflammation is an important contributor to neuronal pathology and death in neurodegenerative diseases and neuronal injury. Therapeutic interventions blocking the activity of the inflammatory kinase IKKβ, a key regulator of neuroinflammatory pathways, is protective in several animal models of neurodegenerative disease and neuronal injury. In Huntington's disease (HD), however, significant questions exist as to the impact of blocking or diminishing the activity of IKKβ on HD pathology given its potential role in Huntingtin (HTT) degradation. In cell culture, IKKβ phosphorylates HTT serine (S) 13 and activates HTT degradation, a process that becomes impaired with polyQ expansion. To investigate the in vivo relationship of IKKβ to HTT S13 phosphorylation and HD progression, we crossed conditional tamoxifen-inducible IKKβ knockout mice with R6/1 HD mice. Behavioral assays in these mice showed a significant worsening of HD pathological phenotypes. The increased behavioral pathology correlated with reduced levels of endogenous mouse full-length phospho-S13 HTT, supporting the importance of IKKβ in the phosphorylation of HTT S13 in vivo. Notably, many striatal autophagy genes were up-regulated in HD vs. control mice; however, IKKβ knockout partially reduced this up-regulation in HD, increased striatal neurodegeneration, and enhanced an activated microglial response. We propose that IKKβ is protective in striatal neurons early in HD progression via phosphorylation of HTT S13. As IKKβ is also required for up-regulation of some autophagy genes and HTT is a scaffold for selective autophagy, IKKβ may influence autophagy through multiple mechanisms to maintain healthy striatal function, thereby reducing neuronal degeneration to slow HD onset.
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