| 摘要(英) |
The abundant accumulation of inclusion bodies containing polyglutamine (polyQ)-expanded mutant huntingtin (mHTT) aggregates is considered as the key pathological event in Huntington’s disease (HD). Literatures have reported that molecular chaperones participate in multiple cellular processes including assisting the folding of newly translated/damaged polypeptides and clearance of the misfolded proteins. Here, we show that Trigger factor (TF), a ribosome-associated chaperone responsible for facilitating the folding of nascent polypeptides in prokaryotes, is able to impact mHTT aggregation in vitro and in vivo.First, we applied GST-HTT polyQ protein system to explore the influence of TF and DnaK, a classical chaperone, in the aggregation process. Our result showed both TF and DnaK significantly reduced HTT(Q)43 aggregates as examined by filter retardation assay. Through transmission electron microscopy (TEM) observation, the mHTT aggregation process was retarded in the presence of TF similar as DnaK. We further examined the biological role of TF in mHTT-expressing N2A cells. Strikingly, we discovered mHTT oligomers were decreased in presence of TF. Furthermore, TF showed increased cell viability and neurite outgrowth in mHTT-expressing cells. Taken these together, we discovered a novel function of TF in modulating the oligomerization/aggregation process, which may benefit developments in HD therapeutic strategies in the future. |
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