pS421 huntingtin modulates mitochondrial phenotypes and confers neuroprotection in an HD hiPSC model.
pS421 huntingtin modulates mitochondrial phenotypes and confers neuroprotection in an HD hiPSC model.
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DOI：
10.1038/s41419-020-02983-z
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发表时间：
2020-09-25
影响因子：
9
通讯作者：
Pouladi MA
中科院分区：
文献类型：
--
作者：
Xu X;Ng B;Sim B;Radulescu CI;Yusof NABM;Goh WI;Lin S;Lim JSY;Cha Y;Kusko R;Kay C;Ratovitski T;Ross C;Hayden MR;Wright G;Pouladi MA
Huntington disease (HD) is a hereditary neurodegenerative disorder caused by mutant huntingtin (mHTT). Phosphorylation at serine-421 (pS421) of mHTT has been shown to be neuroprotective in cellular and rodent models. However, the genetic context of these models differs from that of HD patients. Here we employed human pluripotent stem cells (hiPSCs), which express endogenous full-length mHTT. Using genome editing, we generated isogenic hiPSC lines in which the S421 site in mHTT has been mutated into a phospho-mimetic aspartic acid (S421D) or phospho-resistant alanine (S421A). We observed that S421D, rather than S421A, confers neuroprotection in hiPSC-derived neural cells. Although we observed no effect of S421D on mHTT clearance or axonal transport, two aspects previously reported to be impacted by phosphorylation of mHTT at S421, our analysis revealed modulation of several aspects of mitochondrial form and function. These include mitochondrial surface area, volume, and counts, as well as improved mitochondrial membrane potential and oxidative phosphorylation. Our study validates the protective role of pS421 on mHTT and highlights a facet of the relationship between mHTT and mitochondrial changes in the context of human physiology with potential relevance to the pathogenesis of HD.
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DOI：
10.1177/1073858410390378
发表时间：
2011-10
期刊：
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry
影响因子：
--
作者：
Ehrnhoefer DE;Sutton L;Hayden MR
通讯作者：
Hayden MR
影响因子：
8.8
作者：
Ooi, Jolene;Langley, Sarah R.;Pouladi, Mahmoud A.
通讯作者：
Pouladi, Mahmoud A.
影响因子：
4.8
作者：
Arbez, Nicolas;Ratovitski, Tamara;Ross, Christopher A.
通讯作者：
Ross, Christopher A.
影响因子：
23.9
作者：
通讯作者：
--
影响因子：
14.9
作者：
Aras S;Pak O;Sommer N;Finley R Jr;Hüttemann M;Weissmann N;Grossman LI
通讯作者：
Grossman LI