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Migazzi A, Scaramuzzino C, Anderson EN, et al. Huntingtin-mediated axonal transport requires arginine methylation by PRMT6. Cell Rep. 2021;35(2):108980doi: 10.1016/j.celrep.2021.108980.
Migazzi, A., Scaramuzzino, C., Anderson, E. N., Tripathy, D., Hernández, I. H., Grant, R. A., Roccuzzo, M., Tosatto, L., Virlogeux, A., Zuccato, C., Caricasole, A., Ratovitski, T., Ross, C. A., Pandey, U. B., Lucas, J. J., Saudou, F., Pennuto, M., & Basso, M. (2021). Huntingtin-mediated axonal transport requires arginine methylation by PRMT6. Cell reports, 35(2), 108980. https://doi.org/10.1016/j.celrep.2021.108980
Migazzi, Alice, et al. "Huntingtin-mediated axonal transport requires arginine methylation by PRMT6." Cell reports vol. 35,2 (2021): 108980. doi: https://doi.org/10.1016/j.celrep.2021.108980
Migazzi A, Scaramuzzino C, Anderson EN, Tripathy D, Hernández IH, Grant RA, Roccuzzo M, Tosatto L, Virlogeux A, Zuccato C, Caricasole A, Ratovitski T, Ross CA, Pandey UB, Lucas JJ, Saudou F, Pennuto M, Basso M. Huntingtin-mediated axonal transport requires arginine methylation by PRMT6. Cell Rep. 2021 Apr 13;35(2):108980. doi: 10.1016/j.celrep.2021.108980. PMID: 33852844; PMCID: PMC8132453.
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Cell Rep. 2021 Apr 13;35(2):108980. doi: 10.1016/j.celrep.2021.108980.

Huntingtin-mediated axonal transport requires arginine methylation by PRMT6.

Cell reports

Alice Migazzi, Chiara Scaramuzzino, Eric N Anderson, Debasmita Tripathy, Ivó H Hernández, Rogan A Grant, Michela Roccuzzo, Laura Tosatto, Amandine Virlogeux, Chiara Zuccato, Andrea Caricasole, Tamara Ratovitski, Christopher A Ross, Udai B Pandey, José J Lucas, Frédéric Saudou, Maria Pennuto, Manuela Basso

Affiliations

  1. Laboratory of Transcriptional Neurobiology, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento 38123, Italy; Dulbecco Telethon Institute, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento 38123, Italy; Department of Biomedical Sciences (DBS), University of Padova, Padova 35131, Italy.
  2. Univ. Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, GIN, Grenoble 38000, France.
  3. Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA.
  4. Laboratory of Transcriptional Neurobiology, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento 38123, Italy.
  5. Centro de Biología Molecular "Severo Ochoa" (CBMSO) CSIC/UAM, Madrid, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid 28029, Spain.
  6. Advanced Imaging Core Facility, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento 38123, Italy.
  7. Institute of Biophysics, National Research Council (CNR) Trento unit, Trento 38123, Italy.
  8. Department of Biosciences, University of Milan, Milan, Italy; Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," Milan 20122, Italy.
  9. Department of Neuroscience, IRBM S.p.A., Rome 00071, Italy.
  10. Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  11. Univ. Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, GIN, Grenoble 38000, France. Electronic address: [email protected].
  12. Dulbecco Telethon Institute, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento 38123, Italy; Department of Biomedical Sciences (DBS), University of Padova, Padova 35131, Italy; Veneto Institute of Molecular Medicine (VIMM), via Orus 2, Padova 35129, Italy; Padova Neuroscience Center (PNC), Padova 35131, Italy; Myology Center (CIR-Myo), Padova 35131, Italy. Electronic address: [email protected].
  13. Laboratory of Transcriptional Neurobiology, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento 38123, Italy. Electronic address: [email protected].

PMID: 33852844 PMCID: PMC8132453 DOI: 10.1016/j.celrep.2021.108980

Abstract

The huntingtin (HTT) protein transports various organelles, including vesicles containing neurotrophic factors, from embryonic development throughout life. To better understand how HTT mediates axonal transport and why this function is disrupted in Huntington's disease (HD), we study vesicle-associated HTT and find that it is dimethylated at a highly conserved arginine residue (R118) by the protein arginine methyltransferase 6 (PRMT6). Without R118 methylation, HTT associates less with vesicles, anterograde trafficking is diminished, and neuronal death ensues-very similar to what occurs in HD. Inhibiting PRMT6 in HD cells and neurons exacerbates mutant HTT (mHTT) toxicity and impairs axonal trafficking, whereas overexpressing PRMT6 restores axonal transport and neuronal viability, except in the presence of a methylation-defective variant of mHTT. In HD flies, overexpressing PRMT6 rescues axonal defects and eclosion. Arginine methylation thus regulates HTT-mediated vesicular transport along the axon, and increasing HTT methylation could be of therapeutic interest for HD.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords: Huntington’s disease; PRMT2; PRMT6; arginine methylation; axonal transport; huntingtin; neurodegenerative diseases; neuronal death; protein arginine methyltransfearases; protein post-translational modification

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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