| First Author | Ochaba J | Year | 2019 |
| Journal | Proc Natl Acad Sci U S A | Volume | 116 |
| Issue | 22 | Pages | 10952-10961 |
| PubMed ID | 31088970 | Mgi Jnum | J:276525 |
| Mgi Id | MGI:6307472 | Doi | 10.1073/pnas.1814246116 |
| Citation | Ochaba J, et al. (2019) IKKbeta slows Huntington's disease progression in R6/1 mice. Proc Natl Acad Sci U S A 116(22):10952-10961 |
| abstractText | 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 IKKbeta, 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 IKKbeta on HD pathology given its potential role in Huntingtin (HTT) degradation. In cell culture, IKKbeta phosphorylates HTT serine (S) 13 and activates HTT degradation, a process that becomes impaired with polyQ expansion. To investigate the in vivo relationship of IKKbeta to HTT S13 phosphorylation and HD progression, we crossed conditional tamoxifen-inducible IKKbeta 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 IKKbeta in the phosphorylation of HTT S13 in vivo. Notably, many striatal autophagy genes were up-regulated in HD vs. control mice; however, IKKbeta knockout partially reduced this up-regulation in HD, increased striatal neurodegeneration, and enhanced an activated microglial response. We propose that IKKbeta is protective in striatal neurons early in HD progression via phosphorylation of HTT S13. As IKKbeta is also required for up-regulation of some autophagy genes and HTT is a scaffold for selective autophagy, IKKbeta may influence autophagy through multiple mechanisms to maintain healthy striatal function, thereby reducing neuronal degeneration to slow HD onset. |
