Interplay between TDP-43 and FUS in protein assemblies-Influence of mRNA on the aggregation process

Clément Demongin (1) , Guillaume Lambert (1) , Vandana Joshi (1) , David Pastre (1) , Loic Hamon (1)

1 SABNP - Structure et activité des biomolécules normales et pathologiques

TDP43 and FUS are 2 RNA Binding Proteins (RBP) involved in neurodegenerative diseases. These 2 nuclear proteins are very similar in structure and function; they both harbor RRM (RNA Recognitions Motif) to bind to RNA, and a domain of low complexity promoting protein-protein interaction and potentially, aggregation. They are involved in several mRNA-related process as RNA biogenesis, transport, and splicing. TDP-43 targets more than 6000 mRNA thanks to its RRMs with specificity towards GU motif while FUS interact with broad varieties of mRNA through its ZnF, RGG motifs and RRM without any specific nucleotide sequence. Despite this difference in RNA interaction mode, these proteins promote the formation of mRNA rich compartments like stress granules, drosha complexes, splicing complexes… via the process of liquid-liquid phase separation (LLPS), and within these structures, they accumulate on common RNA targets. Such proximity in functions and localization point toward an interplay between FUS and TDP-43. Here, we analyze their ability to mix or phase separate in cellular context using the microtubule bench technology. Then we reveal the ultrastructure of pure and mixed TDP43 and FUS assemblies as well as the influence of RNA.

Mots clés: RNA Binding Protein; Neurodegenerative Diseases; FUS; TDP-43

Domaines: Sciences du Vivant [q-bio]

Clément Demongin, Guillaume Lambert, Vandana Joshi, David Pastre, Loic Hamon. Interplay between TDP-43 and FUS in protein assemblies-Influence of mRNA on the aggregation process. Molecular Neurodegeneration and Therapeutic Approaches – Virtual Event, Jan 2021, Online, France. 2021. ⟨hal-03195903⟩