Annuaire
Mutant Huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease.
Nat Commun, 12(1):1461.
The polyglutamine expansion of huntingtin (mHTT) causes Huntington disease (HD) andneurodegeneration, but the mechanisms remain unclear. Here, we found that mHttpromotes ribosome stalling and suppresses protein synthesis in mouse HD striatalneuronal cells. Depletion of mHtt enhances protein synthesis and increases the speedof ribosomal translocation, while mHtt directly inhibits protein synthesis in vitro.Fmrp, a known regulator of ribosome stalling, is upregulated in HD, but itsdepletion has no discernible effect on protein synthesis or ribosome stalling in HDcells. We found interactions of ribosomal proteins and translating ribosomes withmHtt. High-resolution global ribosome footprint profiling (Ribo-Seq) and mRNA-Seqindicates a widespread shift in ribosome occupancy toward the 5' and 3' end andunique single-codon pauses on selected mRNA targets in HD cells, compared tocontrols. Thus, mHtt impedes ribosomal translocation during translation elongation,a mechanistic defect that can be exploited for HD therapeutics.
Actions sur le document
