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

[img] Text
Suárez-Calvet 2016.pdf - Published Version
Restricted to registered users only until 20 February 2020.
Available under License Publisher holds Copyright.

Download (4MB) | Request a copy

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Departement of Chemistry and Biochemistry

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Reber, Stefan; Jutzi, Daniel and Ruepp, Marc-David

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

0001-6322

Publisher:

Springer

Funders:

[99] NOMIS
[100] Holcim
[UNSPECIFIED] Fondation Dufloteau

Language:

English

Submitter:

Stefan Reber

Date Deposited:

07 Jun 2018 13:03

Last Modified:

26 Oct 2019 23:21

Publisher DOI:

10.1007/s00401-016-1544-2

PubMed ID:

26895297

BORIS DOI:

10.7892/boris.116504

URI:

https://boris.unibe.ch/id/eprint/116504

Actions (login required)

Edit item Edit item
Provide Feedback