IKKβ slows Huntington’s disease progression in R6/1 mice

• DOI: 10.1073/pnas.1814246116
• Publication Date: 2019-05-14T22:18:10Z
• Authors: Joseph Ochaba; Gianna Fote; Marketta Kachemov; Soe Thein; Sylvia Y. Yeung; Alice L. Lau; Sarah Hernandez; Ryan G. Lim; Malcolm Casale; Michael J. Neel; Edwin S. Monuki; Jack Reidling; David E. Housman; Leslie M. Thompson; Joan S. Steffan
• Keywords: Huntington's Disease; Male; autophagy; IκB kinase; huntingtin; Knockout; 610; Neurodegenerative; Mice; 03 medical and health sciences; Rare Diseases; Autophagy; 2.1 Biological and endogenous factors; Animals; Phosphorylation; Mice, Knockout; Huntingtin Protein; 0303 health sciences; Biomedical and Clinical Sciences; Animal; Neurosciences; neurodegeneration; Huntington's disease; Biological Sciences; Corpus Striatum; Brain Disorders; I-kappa B Kinase; 3. Good health; Disease Models, Animal; Orphan Drug; Huntington Disease; PNAS Plus; I kappa B kinase; Neurological; Disease Models; Disease Progression; Biochemistry and Cell Biology; Microglia; Huntington’s disease

Significance Huntington’s disease (HD) is a devastating neurodegenerative disorder caused by expansion of a polyglutamine repeat within the huntingtin (HTT) protein. A normal function of HTT is that of a scaffold for selective autophagy, a mechanism of protein and organelle degradation by the lysosome required for neuronal health. Here, we show that the inflammatory IκB kinase (IKK) kinase subunit IKKβ may function in vivo to regulate autophagy through direct phosphorylation of HTT at serine 13 and through the activation of autophagy gene expression. IKKβ is required to slow HD behavioral progression and to suppress neurodegeneration and microglial activation in HD transgenic mice. Our work suggests that the early activation of IKK may be protective to activate autophagy, thereby slowing HD progression.