Journal
CELL REPORTS
Volume 35, Issue 2, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.108980
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Funding
- Telethon-Italy
- Autonomous Province of Trento [TCP12013]
- Association Francaise contre les Myopathies [AFM22221]
- PRIN-MUR [2017F2A2C5]
- National Institutes of Health [1R21NS111768-01]
- PROGRAM RARE DISEASES CNCCS-Scarl-Pomezia
- FONDAZIONE AIRC-Italy [24423]
- Alzheimer Trento Onlus with the legato Baldrachi
- Agence Nationale de la Recherche [ANR-15-JPWG-0003-05 JPND CIRCPROT, ANR18-CE16-0009-01 AXYON]
- Federation pour la Recherche sur le Cerveau
- AGEMED program from Inserm
- NeuroCoG [ANR-15-IDEX-02]
- Spanish Ministry of Science, Innovation and Universities (MCIU/AEI/FEDER-UE) [RTI2018096322-B-I00]
- University of Trento
- Boehringer Ingelheim Fonds travel grant
- EMBO STF [STF8140]
- FRM
- EMBO LTF [ALTF 693-2015]
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Arginine methylation plays a crucial role in regulating the vesicular transport of huntingtin protein along the axon, and increasing HTT methylation could be a potential therapeutic target for Huntington's disease.
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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