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Updated: Nov 9, 2025

Quantitative Methods to Study Protein Arginine Methyltransferase 1-9 Activity in Cells
Published on: August 7, 2021
Huntingtin-mediated axonal transport requires arginine methylation by PRMT6
Alice Migazzi1, Chiara Scaramuzzino2, Eric N Anderson3
1Laboratory 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.
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.
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