Monomethylated and unmethylated FUS exhibit increased binding to Transportin and distinguish FTLD-FUS from ALS-FUS

Suárez-Calvet, Marc; Neumann, Manuela; Arzberger, Thomas; Abou-Ajram, Claudia; Funk, Eva; Hartmann, Hannelore; Edbauer, Dieter; Kremmer, Elisabeth; Göbl, Christoph; Resch, Moritz; Bourgeois, Benjamin; Madl, Tobias; Reber, Stefan; Jutzi, Daniel; Ruepp, Marc-David; Mackenzie, Ian R. A.; Ansorge, Olaf; Dormann, Dorothee; Haass, Christian (2016). Monomethylated and unmethylated FUS exhibit increased binding to Transportin and distinguish FTLD-FUS from ALS-FUS. Acta neuropathologica, 131(4), pp. 587-604. Springer 10.1007/s00401-016-1544-2

Text Suárez-Calvet 2016.pdf - Published Version Available under License Publisher holds Copyright. Download (4MB)

Deposition of the nuclear DNA/RNA-binding protein Fused in sarcoma (FUS) in cytosolic inclusions is a common hallmark of some cases of frontotemporal lobar degeneration (FTLD-FUS) and amyotrophic lateral sclero- sis (ALS-FUS). Whether both diseases also share common pathological mechanisms is currently unclear. Based on our previous finding that FUS deposits are hypomethylated in FTLD-FUS but not in ALS-FUS, we have now investigated whether genetic or pharmacological inactivation of Pro- tein arginine methyltransferase 1 (PRMT1) activity results in unmethylated FUS or in alternatively methylated forms of FUS. To do so, we generated FUS-specific monoclonal antibodies that specifically recognize unmethylated argi- nine (UMA), monomethylated arginine (MMA) or asym- metrically dimethylated arginine (ADMA). Loss of PRMT1 indeed not only results in an increase of UMA FUS and a decrease of ADMA FUS, but also in a significant increase of MMA FUS. Compared to ADMA FUS, UMA and MMA FUS exhibit much higher binding affinities to Transportin-1, the nuclear import receptor of FUS, as measured by pull- down assays and isothermal titration calorimetry. Moreover, we show that MMA FUS occurs exclusively in FTLD-FUS, but not in ALS-FUS. Our findings therefore provide addi- tional evidence that FTLD-FUS and ALS-FUS are caused by distinct disease mechanisms although both share FUS deposits as a common denominator.

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