ArticleCell death & disease2020
pS421 huntingtin modulates mitochondrial phenotypes and confers neuroprotection in an HD hiPSC model.
Article in Cell death & disease, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
7 citing papers in PubMed, 19 citations in OpenAlex.
- Post-Translational Modifications of Huntingtin: Mechanistic Insights and Therapeutic Opportunities in Huntington's Disease.International journal of molecular sciences · 2025Review
- Huntingtin contains an ubiquitin-binding domain and regulates lysosomal targeting of mitochondrial and RNA-binding proteins.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- CHCHD2 up-regulation in Huntington disease mediates a compensatory protective response against oxidative stress.Cell death & disease · 2024Article
- IKBKB reduces huntingtin aggregation by phosphorylating serine 13 via a non-canonical IKK pathway.Life science alliance · 2023Article
- Huntingtin S421 phosphorylation increases kinesin and dynein engagement on early endosomes and lysosomes.Biophysical journal · 2023Article
- Protein Kinase CK2 and Its Potential Role as a Therapeutic Target in Huntington's Disease.Biomedicines · 2022Review
- Non-Cell Autonomous and Epigenetic Mechanisms of Huntington's Disease.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
16 authors at 6 institutions in 4 countries.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.