Evidence map›Paper›PMID 34888656›Full record

ArticleHuman molecular genetics2022

Interaction of huntingtin with PRMTs and its subsequent arginine methylation affects HTT solubility, phase transition behavior and neuronal toxicity.

Tamara Ratovitski, Mali Jiang, Robert N O'Meally, Priyanka Rauniyar, Ekaterine Chighladze, Anikó Faragó, Siddhi V Kamath, Jing Jin, Alexey V Shevelkin, Robert N Cole and 1 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Human molecular genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.

0numbers the graph read from it
0cells of the map it votes in
24citing papers in PubMed
3.0field-weighted citation impact, top 8% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

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.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

24 citing papers in PubMed, 33 citations in OpenAlex.

  1. Article
  2. Review
  3. Article
  4. Review
  5. PRMT3 and CARM1: Emerging Epigenetic Targets in Cancer.Journal of cellular and molecular medicine · 2025
    Review
  6. Review
  7. Review
  8. Article
  9. Review
  10. Article
  11. Review
  12. Review
  13. Review
  14. Article
  15. Review
  16. Article
  17. Article
  18. Review
  19. Review
  20. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 1 institution in 1 country.

Tamara RatovitskiDivision of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.ORCID 0000-0003-4020-5644
Mali JiangDivision of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Robert N O'MeallyMass Spectrometry and Proteomics Facility, Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Priyanka RauniyarDivision of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Ekaterine ChighladzeDivision of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Anikó FaragóDivision of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Siddhi V KamathDivision of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Jing JinDivision of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Alexey V ShevelkinDivision of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Robert N ColeMass Spectrometry and Proteomics Facility, Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Christopher A RossDivision of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Johns Hopkins University · US

Funding

Validation of Novel Pathogenic Post-Translational Modifications of Huntingtin, and of Modifying Enzymes as Therapeutic Targets for Huntington's DiseaseR01NS086452 · NINDS · JOHNS HOPKINS UNIVERSITY · PI ROSS, CHRISTOPHER A · 2014 to 2023
$6.2M
Targeting Protein Arginine Methylation in HDR21NS109412 · NINDS · JOHNS HOPKINS UNIVERSITY · PI RATOVITSKI, TAMARA · 2019 to 2020
$450k
NINDS NIH HHS R01 NS086452NINDS NIH HHS R21 NS109412
6 · The paper itself

Abstract

Huntington's disease (HD) is an incurable neurodegenerative disorder caused by a CAG expansion in the huntingtin gene (HTT). Post-translational modifications of huntingtin protein (HTT), such as phosphorylation, acetylation and ubiquitination, have been implicated in HD pathogenesis. Arginine methylation/dimethylation is an important modification with an emerging role in neurodegeneration; however, arginine methylation of HTT remains largely unexplored. Here we report nearly two dozen novel arginine methylation/dimethylation sites on the endogenous HTT from human and mouse brain and human cells suggested by mass spectrometry with data-dependent acquisition. Targeted quantitative mass spectrometry identified differential arginine methylation at specific sites in HD patient-derived striatal precursor cell lines compared to normal controls. We found that HTT can interact with several type I protein arginine methyltransferases (PRMTs) via its N-terminal domain. Using a combination of in vitro methylation and cell-based experiments, we identified PRMT4 (CARM1) and PRMT6 as major enzymes methylating HTT at specific arginines. Alterations of these methylation sites had a profound effect on biochemical properties of HTT rendering it less soluble in cells and affected its liquid-liquid phase separation and phase transition patterns in vitro. We found that expanded HTT 1-586 fragment can form liquid-like assemblies, which converted into solid-like assemblies when the R200/205 methylation sites were altered. Methyl-null alterations increased HTT toxicity to neuronal cells, while overexpression of PRMT 4 and 6 was beneficial for neuronal survival. Thus, arginine methylation pathways that involve specific HTT-modifying PRMT enzymes and modulate HTT biochemical and toxic properties could provide targets for HD-modifying therapies.

Indexed as

ArginineHuntington DiseaseAnimalsHumansHuntingtin ProteinMethylationMiceNuclear ProteinsProtein-Arginine N-MethyltransferasesProtein Processing, Post-TranslationalSolubilityArginineHTT protein, humanHtt protein, mouseHuntingtin ProteinNuclear ProteinsPRMT6 protein, humanProtein-Arginine N-Methyltransferases

Identifiers

PMID34888656
PMCPMC9122652
OpenAlexW4200464141

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

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.