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Ratovitski T, Jiang M, O'Meally RN, et al. Interaction of huntingtin (HTT) with PRMTs and its subsequent arginine methylation affects HTT solubility, phase transition behavior and neuronal toxicity. Hum Mol Genet. 2021;doi: 10.1093/hmg/ddab351.
Ratovitski, T., Jiang, M., O'Meally, R. N., Rauniyar, P., Chighladze, E., Faragó, A., Kamath, S. V., Jin, J., Shevelkin, A. V., Cole, R. N., & Ross, C. A. (2021). Interaction of huntingtin (HTT) with PRMTs and its subsequent arginine methylation affects HTT solubility, phase transition behavior and neuronal toxicity. Human molecular genetics, . https://doi.org/10.1093/hmg/ddab351
Ratovitski, Tamara, et al. "Interaction of huntingtin (HTT) with PRMTs and its subsequent arginine methylation affects HTT solubility, phase transition behavior and neuronal toxicity." Human molecular genetics vol. (2021). doi: https://doi.org/10.1093/hmg/ddab351
Ratovitski T, Jiang M, O'Meally RN, Rauniyar P, Chighladze E, Faragó A, Kamath SV, Jin J, Shevelkin AV, Cole RN, Ross CA. Interaction of huntingtin (HTT) with PRMTs and its subsequent arginine methylation affects HTT solubility, phase transition behavior and neuronal toxicity. Hum Mol Genet. 2021 Dec 09; doi: 10.1093/hmg/ddab351. Epub 2021 Dec 09. PMID: 34888656.
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Hum Mol Genet. 2021 Dec 09; doi: 10.1093/hmg/ddab351. Epub 2021 Dec 09.

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

Human molecular genetics

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, Christopher A Ross

Affiliations

  1. Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 8-121, Baltimore, MD21287.
  2. Mass Spectrometry and Proteomics Facility, Department of Biological Chemistry, Johns Hopkins University School of Medicine, 733 N. Broadway Street, Suite 371 BRB Baltimore, MD21287.
  3. Departments of Neurology, Neuroscience and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD21287.

PMID: 34888656 DOI: 10.1093/hmg/ddab351

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 (DDA). 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 (LLPS) 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.

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