Cellular modifiers of TDP-43 phase transition and cytoplasmic aggregation

TAR DNA-binding protein 43 (TDP-43), an RNA-binding protein, can form liquid-like assemblies within the nucleus, which may affect its aggregation and neurotoxicity. However, the factors that control the transition of TDP-43 from a liquid to a solid phase are not well understood. In this study, researchers employed both chemical and genome-wide genetic screens to uncover cellular factors that influence the phase behavior of an RNA-binding-defective TDP-43 mutant.

The screens revealed several cellular processes that regulate TDP-43 phase behavior, including RNA splicing, protein translation, proteostasis imbalance, and nuclear export. To better understand these mechanisms, the researchers created a semi-permeabilized cell system that approximates the TDP-43 phase transition in a laboratory setting.

They found that inhibiting nuclear export, the process by which proteins and RNA molecules move between the nucleus and the cytoplasm, alters the nuclear environment in a way that promotes the liquid-like phase of TDP-43 and reduces its aggregation.

The implications of these findings extend beyond the lab, as the researchers tested their approach in a brain organoid model carrying an ALS-associated mutation. In this model, inhibiting nuclear export reduced the accumulation of a toxic form of TDP-43 called phospho-TDP-43. This discovery offers new insights into the link between nuclear transport and TDP-43 phase dynamics, opening doors for further investigation into the underlying causes of ALS and potential therapeutic targets.