12.07.2023The Polymenidou group shows that loss of TDP-43 oligomerization or RNA binding elicits distinct protein aggregation patterns

In disease, the RNA-binding protein TAR DNA-binding protein 43 (TDP-43) is known to form cytoplasmic or intranuclear inclusions, but how TDP-43 transitions from physiological to pathological states remains poorly understood. In this work, the Polymenidou group unravels the origins of heterogeneous pathological species reminiscent of those occurring in TDP-43 proteinopathy patients. By using human neurons and cell lines with near-physiological expression levels, oligomerization and RNA binding are shown to govern TDP-43 stability, splicing functionality, LLPS, and subcellular localization. Monomeric TDP-43 is found to form inclusions in the cytoplasm, whereas its RNA binding-deficient counterpart aggregates in the nucleus. These differentially localized aggregates emerge via distinct pathways: LLPS-driven aggregation in the nucleus and aggresome-dependent inclusion formation in the cytoplasm.
See Pérez-Berlanga et al., The EMBO Journal