Article Dans Une Revue Nature Communications Année : 2026

From TDP-43/RNA complex formation to disease-linked TDP-43 aggregation through a structural and cellular approach

Résumé

Many RNA-binding proteins (RBP) have been associated to several neurodegenerative diseases for which RBP-rich cytoplasmic inclusions represent a major histological hallmark. However, among RBPs, the occurrence with which TDP-43, a nuclear mRNA-binding protein, is detected in cytoplasmic inclusions is exceptionally high. To unravel the underlying mechanisms, we focus our analysis on the structured N-terminal domain (NTD) of TDP-43, which is distinct among RBPs as this domain mostly initiates TDP-43 homotypic interactions. Through an in depth structural analysis, we successively show that the cooperative binding of TDP-43 along long GU-rich intronic sequences antagonizes NTD/NTD interactions between adjacent TDP-43 along mRNA. In contrast, the TDP-43 cooperativity facilitates NTD/NTD interactions between TDP-43 located on distinct GU-rich sequences. We hypothesize that NTD/NTD interactions between distinct GU-rich sequences efficiently allow the compaction of long introns in neurons under physiological conditions. However, when the binding of TDP-43 to RNA is discontinuous because of a lack of cooperativity, aberrant NTD/NTD interactions between adjacent TDP-43 take place, promoting the aggregation of TDP-43 RRMs (RNA Recognition Motifs) under stress conditions. Altogether, we provide a detailed view of the physiological assembly of TDP-43 on introns and the putative weaknesses of TDP-43 that makes it distinct in its propensity for aggregation compared to other RBPs.

Dates et versions

hal-05517675 , version 1 (18-02-2026)

Identifiants

Citer

Yitian Feng, Vandana Joshi, Serhii Pankivskyi, Marie-Jeanne Clément, Juan-Carlos Rengifo-Gonzalez, et al.. From TDP-43/RNA complex formation to disease-linked TDP-43 aggregation through a structural and cellular approach. Nature Communications, In press, 17, pp.1631. ⟨10.1038/s41467-026-68346-y⟩. ⟨hal-05517675⟩
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