Huntington disease (HD) is caused by the accumulation of mutant huntingtin (mHTT) that contains an expanded polyglutamine (polyQ) tract. Through screening, Li et al. identified four compounds that tether mHTT, but not wild-type HTT, to the autophagy-related protein LC3. The compounds drove autophagy-dependent reductions of mHTT in neurons from a mouse model of HD. Intraperitoneal delivery of two of the compounds reduced cortical mHTT levels in HD mice and improved behavioural deficits in fly and mouse models of HD. Allele-specific linker compounds might have potential in treating HD and other polyQ disorders.
Li, Z. et al. Allele-selective lowering of mutant HTT protein by HTT–LC3 linker compounds. Nature 575, 203–209 (2019)
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Bray, N. Hunting out mutant huntingtin. Nat Rev Neurosci 21, 3 (2020). https://doi.org/10.1038/s41583-019-0248-8