期刊
HUMAN MOLECULAR GENETICS
卷 17, 期 24, 页码 3837-3846出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddn281
关键词
-
资金
- Agence Nationale pour la Recherche - Maladies Rares [ANR-MRAR-018-01]
- Association pour la Recherche sur le Cancer [3665]
- Fondation pour la Recherche Medicale
- Fondation BNP Paribas
- HighQ Foundation
- FRM
- Swiss National Science Foundation
- MRT
- CNRS
- Ile de France
Huntingtin (htt), the protein mutated in Huntington's disease, is a positive regulatory factor for vesicular transport whose function is lost in disease. Here, we demonstrate that phosphorylation of htt at serine 421 (S421) restores its function in axonal transport. Using a strategy involving RNA (ribonucleic acid) interference and re-expression of various constructs, we show that polyQ (polyglutamine)-htt is unable to promote transport of brain-derived neurotrophic factor (BDNF)-containing vesicles, but polyQ-htt constitutively phosphorylated at S421 is as effective as the wild-type (wt) as concerns transport of these vesicles. The S421 phosphorylated polyQ-htt displays the wt function of inducing BDNF release. Phosphorylation restores the interaction between htt and the p150(Glued) subunit of dynactin and their association with microtubules in vitro and in cells. We also show that the IGF-1 (insulin growth factor type I)/Akt pathway by promoting htt phosphorylation compensates for the transport defect. This is the first description of a mechanism that restores the htt function altered in disease.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据