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000163509 041__ $$aEnglish
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000163509 1001_ $$0P:(DE-2719)2811882$$aGruijs da Silva, Lara Aletta$$b0$$udzne
000163509 245__ $$aDisease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation.
000163509 260__ $$aHoboken, NJ [u.a.]$$bWiley$$c2022
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000163509 520__ $$aPost-translational modifications (PTMs) have emerged as key modulators of protein phase separation and have been linked to protein aggregation in neurodegenerative disorders. The major aggregating protein in amyotrophic lateral sclerosis and frontotemporal dementia, the RNA-binding protein TAR DNA-binding protein (TDP-43), is hyperphosphorylated in disease on several C-terminal serine residues, a process generally believed to promote TDP-43 aggregation. Here, we however find that Casein kinase 1δ-mediated TDP-43 hyperphosphorylation or C-terminal phosphomimetic mutations reduce TDP-43 phase separation and aggregation, and instead render TDP-43 condensates more liquid-like and dynamic. Multi-scale molecular dynamics simulations reveal reduced homotypic interactions of TDP-43 low-complexity domains through enhanced solvation of phosphomimetic residues. Cellular experiments show that phosphomimetic substitutions do not affect nuclear import or RNA regulatory functions of TDP-43, but suppress accumulation of TDP-43 in membrane-less organelles and promote its solubility in neurons. We speculate that TDP-43 hyperphosphorylation may be a protective cellular response to counteract TDP-43 aggregation.
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000163509 650_7 $$2Other$$aRNA-binding protein
000163509 650_7 $$2Other$$aTDP-43
000163509 650_7 $$2Other$$aneurodegeneration
000163509 650_7 $$2Other$$aphase separation
000163509 650_7 $$2Other$$aphosphorylation
000163509 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000163509 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000163509 650_2 $$2MeSH$$aDNA-Binding Proteins: metabolism
000163509 650_2 $$2MeSH$$aFrontotemporal Dementia
000163509 650_2 $$2MeSH$$aHumans
000163509 650_2 $$2MeSH$$aProtein Aggregates
000163509 650_2 $$2MeSH$$aRNA-Binding Proteins: genetics
000163509 650_2 $$2MeSH$$aRNA-Binding Proteins: metabolism
000163509 7001_ $$0P:(DE-2719)9001596$$aSimonetti, Francesca$$b1$$udzne
000163509 7001_ $$aHutten, Saskia$$b2
000163509 7001_ $$0P:(DE-2719)2812261$$aRiemenschneider, Henrick$$b3$$udzne
000163509 7001_ $$aSternburg, Erin L$$b4
000163509 7001_ $$aPietrek, Lisa M$$b5
000163509 7001_ $$00000-0002-8994-9153$$aGebel, Jakob$$b6
000163509 7001_ $$aDötsch, Volker$$b7
000163509 7001_ $$0P:(DE-2719)2231621$$aEdbauer, Dieter$$b8$$udzne
000163509 7001_ $$00000-0001-7768-746X$$aHummer, Gerhard$$b9
000163509 7001_ $$00000-0002-5348-0277$$aStelzl, Lukas S$$b10
000163509 7001_ $$0P:(DE-2719)9000059$$aDormann, Dorothee$$b11$$udzne
000163509 773__ $$0PERI:(DE-600)1467419-1$$a10.15252/embj.2021108443$$n8$$pe108443$$tThe EMBO journal$$v41$$x1460-2075$$y2022
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