SUMMARY
Despite the prominent role of TDP-43 in neurodegeneration, its physiological and pathological functions are not fully understood. Here, we report an unexpected function of TDP-43, which forms dynamic, reversible, droplet-like nuclear bodies (NBs) in response to stress, and the formation of NBs alleviates TDP-43-mediatd cytotoxicity and neurodegeneration in cell and Drosophila models of amyotrophic lateral sclerosis (ALS). Super-resolution microscopy reveals a “core-shell” architecture of TDP-43 NBs, which is maintained by the two RRMs antagonistically. Further, TDP-43 NBs are partially colocalized with nuclear paraspeckles and the paraspeckle scaffolding lncRNA NEAT1 is dramatically upregulated in stressed neurons. Moreover, increase of NEAT1 promotes TDP-43 liquid-liquid phase separation (LLPS) in vitro. Finally, we uncover that the ALS-associated mutation TDP-43D169G impairs NEAT1-induced phase separation, causing a specific defect in the assembly of TDP-43 NBs but not stress granules. Together, our findings propose a stress-mitigating role and mechanism for TDP-43 NBs, whose dysfunction may contribute to ALS pathogenesis.
Highlights (Up to four bullet points. The length of each highlight cannot exceed 85 characters, including spaces)
TDP-43 forms reversible, LD-like NBs alleviating cytotoxicity and neurodegeneration
The two RRMs act antagonistically to maintain a core-shell architecture of TDP-43 NBs
LncRNA NEAT1 is upregulated in stressed neurons, which promotes TDP-43 LLPS
ALS-causing mutation D169G abolishes NEAT1-induced TDP-43 LLPS and NBs