Huntingtin-mediated axonal transport requires arginine methylation by PRMT6

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number108980
JournalCell Reports
Volume35
Issue number2
DOIs
StatePublished - Apr 13 2021

Keywords

  • Huntington's disease
  • PRMT2
  • PRMT6
  • arginine methylation
  • axonal transport
  • huntingtin
  • neurodegenerative diseases
  • neuronal death
  • protein arginine methyltransfearases
  • protein post-translational modification

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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