Loss of TDP-43 oligomerization or RNA binding elicits distinct aggregation patterns

Pérez-Berlanga, Manuela; Wiersma, Vera I; Zbinden, Aurélie; De Vos, Laura; Wagner, Ulrich; Foglieni, Chiara; Mallona, Izaskun; Betz, Katharina M; Cléry, Antoine; Weber, Julien; Guo, Zhongning; Rigort, Ruben; de Rossi, Pierre; Manglunia, Ruchi; Tantardini, Elena; Sahadevan, Sonu; Stach, Oliver; Hruska-Plochan, Marian; Allain, Frederic H-T; Paganetti, Paolo

doi:10.15252/embj.2022111719

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Pérez-Berlanga, M., Wiersma, V. I., Zbinden, A., De Vos, L., Wagner, U., Foglieni, C., Mallona, I., Betz, K. M., Cléry, A., Weber, J., Guo, Z., Rigort, R., de Rossi, P., Manglunia, R., Tantardini, E., Sahadevan, S., Stach, O., Hruska-Plochan, M., Allain, F. H.-T., … Polymenidou, M. (2023). Loss of TDP-43 oligomerization or RNA binding elicits distinct aggregation patterns. The EMBO Journal, 42(17), e111719. https://doi.org/10.15252/embj.2022111719

Abstract

Aggregation of the RNA-binding protein TAR DNA-binding protein 43 (TDP-43) is the key neuropathological feature of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). In physiological conditions, TDP-43 is predominantly nuclear, forms oligomers, and is contained in biomolecular condensates assembled by liquid-liquid phase separation (LLPS). In disease, TDP-43 forms cytoplasmic or intranuclear inclusions. How TDP-43 transitions from physiological to pathological states