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
Affiliations
Alice Migazzi
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
Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA
Debasmita Tripathy
Laboratory of Transcriptional Neurobiology, Department of Cellular, Computational and Integrative Biology – CIBIO, University of Trento, Trento 38123, Italy
Ivó H. Hernández
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
Rogan A. Grant
Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA
Michela Roccuzzo
Advanced Imaging Core Facility, Department of Cellular, Computational and Integrative Biology – CIBIO, University of Trento, Trento 38123, Italy
Laura Tosatto
Institute of Biophysics, National Research Council (CNR) Trento unit, Trento 38123, Italy
Department of Biosciences, University of Milan, Milan, Italy; Istituto Nazionale di Genetica Molecolare “Romeo ed Enrica Invernizzi,” Milan 20122, Italy
Andrea Caricasole
Department of Neuroscience, IRBM S.p.A., Rome 00071, Italy
Tamara Ratovitski
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Christopher A. Ross
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Udai B. Pandey
Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA
José J. Lucas
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
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; Corresponding author
Manuela Basso
Laboratory of Transcriptional Neurobiology, Department of Cellular, Computational and Integrative Biology – CIBIO, University of Trento, Trento 38123, Italy; Corresponding author
Summary: 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.
