Critical impact of lysine 136 in TDP-43 phase separation, compartmentalization, and aggregation in living vertebrates.

ABSTRACT: TDP-43 is a nuclear RNA-binding protein that undergoes liquid-liquid phase separation (LLPS) and forms insoluble aggregates in neurodegenerative diseases. By studying TDP-43 in living vertebrates, we confirmed that TDP-43 undergoes LLPS and forms dynamic biomolecular condensates in spinal motor neurons. We validated in vivo that interfering with the lysine residue at position 136 altered the phase separation behavior of TDP-43 by reducing cytoplasmic mislocalization and aggregation. These alterations were post-translational modification (PTM) independent, highlighting that residue 136 is a key structural regulator of TDP-43 function. We further established an adeno-associated virus (AAV)-mediated expression approach in mice that confirmed altered nuclear condensation characteristics

SUBMITTER: Maurel C 

PROVIDER: S-EPMC12205618 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature