TY - JOUR
T1 - pS421 huntingtin modulates mitochondrial phenotypes and confers neuroprotection in an HD hiPSC model
AU - Xu, Xiaohong
AU - Ng, Bryan
AU - Sim, Bernice
AU - Radulescu, Carola I.
AU - Yusof, Nur Amirah Binte Mohammad
AU - Goh, Wah Ing
AU - Lin, Shuping
AU - Lim, John Soon Yew
AU - Cha, Yoonjeong
AU - Kusko, Rebecca
AU - Kay, Chris
AU - Ratovitski, Tamara
AU - Ross, Christopher
AU - Hayden, Michael R.
AU - Wright, Graham
AU - Pouladi, Mahmoud A.
N1 - Funding Information:
We thank Weiping Yu (Biological Resources Centre, A*STAR) for reagents and members of the Pouladi lab for helpful comments. We thank the NINDS hiPSC Repository for the HD hiPSC lines (CAG180 and CAG33). The work was partly funded by a Strategic Positioning Fund for Genetic Orphan Diseases (SPF2012/ 005) from the Agency for Science Technology and Research (Singapore), and a Tier 1 grant R-172–000–297–112 from the Ministry of Education (Singapore) to M.A.P. C.R. is supported by grants from the CHDI Foundation and the NIH (NINDS grant R01 NS086452). This study was also supported by a grant from the National Natural Science Foundation of China (Grant Number 81901295).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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.
AB - 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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U2 - 10.1038/s41419-020-02983-z
DO - 10.1038/s41419-020-02983-z
M3 - Article
C2 - 32978366
AN - SCOPUS:85091448878
SN - 2041-4889
VL - 11
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 9
M1 - 809
ER -