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SHR Neuro Krebs Kardio Lipid

Suárez-Calvet, M; Neumann, M; Arzberger, T; Abou-Ajram, C; Funk, E; Hartmann, H; Edbauer, D; Kremmer, E; Göbl, C; Resch, M; Bourgeois, B; Madl, T; Reber, S; Jutzi, D; Ruepp, MD; Mackenzie, IR; Ansorge, O; Dormann, D; Haass, C.
Monomethylated and unmethylated FUS exhibit increased binding to Transportin and distinguish FTLD-FUS from ALS-FUS.
Acta Neuropathol. 2016; 131(4):587-604
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Autor/innen der Med Uni Graz:
Madl Tobias
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Abstract:
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 sclerosis (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 Protein 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 arginine (UMA), monomethylated arginine (MMA) or asymmetrically 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 additional evidence that FTLD-FUS and ALS-FUS are caused by distinct disease mechanisms although both share FUS deposits as a common denominator.
Find related publications in this database (using NLM MeSH Indexing)
Amyotrophic Lateral Sclerosis - genetics
Amyotrophic Lateral Sclerosis - metabolism
Animals -
Antibodies - pharmacology
Arginine - metabolism
Cells, Cultured -
Cerebral Cortex - cytology
Embryo, Mammalian -
Embryonic Stem Cells -
Enzyme Inhibitors - pharmacology
Female -
Frontotemporal Lobar Degeneration - genetics
Frontotemporal Lobar Degeneration - metabolism
Humans -
Inclusion Bodies - drug effects
Inclusion Bodies - metabolism
Male -
Methylation -
Mice -
Mice, Inbred C57BL -
Mice, Knockout -
Neurons - drug effects
Neurons - metabolism
Protein Binding - drug effects
Protein Binding - genetics
Protein-Arginine N-Methyltransferases - genetics
Protein-Arginine N-Methyltransferases - metabolism
RNA-Binding Protein FUS - immunology
RNA-Binding Protein FUS - metabolism
Rats -
beta Karyopherins - immunology
beta Karyopherins - metabolism

Find related publications in this database (Keywords)
Frontotemporal lobar degeneration (FTLD)
Amyotrophic lateral sclerosis (ALS)
Fused in sarcoma (FUS)
Arginine methylation
Neurodegeneration
Protein arginine methyltransferase 1 (PRMT1)
Transportin-1
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