Neurology/Neuroscience Research Seminar

Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) disease spectrum. While most ALS cases are sporadic, mutations in TDP-43 can directly cause ALS, likely via a combination of nuclear loss-of-function and cytoplasmic toxic gain-of-function phenotypes. Here we show that several members of the nuclear import receptor (NIR) protein family reduce the formation of pathological TDP-43 aggregates. The NIR karyopherin-β1 (KPNB1) can rescue all hallmarks of TDP-43 pathology, by restoring its solubility and nuclear localization, and reducing neurodegeneration in cellular and animal models of ALS/FTD. Our findings suggest a novel NLS-independent mechanism where, analogous to its canonical role in dissolving the diffusion barrier formed by phenylalanine and glycine-rich nucleoporins (FG-Nups) in the nuclear pore, KPNB1 is recruited into TDP-43/FG-Nup co-aggregates present in TDP-43 proteinopathies and therapeutically reverses their deleterious phase transition and mislocalization, mitigating neurodegeneration.