Chou, C.C., Zhang, Y., Umoh, M.E., Vaughan, S.W., Lorenzini, I., Liu, F., Sayegh, M., Donlin-Asp, P.G., Chen, Y.H., Duong, D.M., Seyfried, N.T., Powers, M.A., Kukar, T., Hales, C.M., Gearing, M., Cairns, N.J., Boylan, K.B., Dickson, D.W., Rademakers, R., Zhang, Y.J., Petrucelli, L., Sattler, R., Zarnescu, D.C., Glass, J.D., Rossoll, W. (2018). TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD.  Nat. Neurosci. 21(2): 228--239.

FBrf0250648

Research paper

The cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a common histopathological hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD). However, the composition of aggregates and their contribution to the disease process remain unknown. Here we used proximity-dependent biotin identification (BioID) to interrogate the interactome of detergent-insoluble TDP-43 aggregates and found them enriched for components of the nuclear pore complex and nucleocytoplasmic transport machinery. Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins and transport factors, and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts and induced pluripotent stem cell-derived neurons. Nuclear pore pathology is present in brain tissue in cases of sporadic ALS and those involving genetic mutations in TARDBP and C9orf72. Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD.

PMC5800968 (PMC) (EuropePMC)