In Huntington’s disease (HD), a genetic mutation expands a polyglutamine repeat sequence within the huntingtin (HTT) protein, causing the protein to misfold and aggregate. In the healthy human brain, HTT facilitates autophagy, a mechanism that delivers harmful proteins and damaged organelles to lysosomes for degradation.
Researchers report a potential relationship between HD pathogenesis and IKKβ—a subunit of the inflammatory IκB kinase complex—that stems from the role of the kinase in HTT phosphorylation and autophagy. Combining IKKβ knockout with an established HD mouse model, the authors demonstrated that loss of IKKβ function reduces HTT phosphorylation in both mutant HD mice and wild-type controls, and that IKKβ knockout exacerbates disease severity in HD mice in concert with decreased levels of endogenous phosphorylated HTT.
The authors also found that the expression of a number of genes with known links to autophagy appear to be upregulated in HD mice relative to controls. However, IKKβ knockout diminished such upregulation in HD mice.
The findings suggest that autophagy imbalance may tip the scale from cell survival to neurodegeneration in HD, and that early intervention via IKK activation may help slow the progression of HD.
https://www.pnas.org/content/early/2019/05/13/1814246116
Autophagy and neurodegeneration in Huntington's disease
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