TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD

Abstract

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 (NPC) and nucleocytoplasmic transport machinery. Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins (Nups) and transport factors (TFs), and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts, and iPSC-derived neurons. Nuclear pore pathology is present in brain tissue from sporadic ALS cases (sALS) and those with genetic mutations in TARDBP (TDP-ALS) and C9orf72 (C9-ALS). Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD.

RNA versus protein toxicity in C9orf72 ALS/FTLD

“…The nuclear shape was slightly abnormal in both C9orf72 and non-hereditary ALS cases. This is consistent with a parallel study showing that nuclear pore defects are not unique for C9orf72 cases but are also directly connected to the TDP-43 pathology in ALS [4].…”

Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology

“…Since TDP-43 pathology has been attributed to nuclear membrane defects and problems with nucleocytoplasmic transport system [13, 35], we first investigated the nuclear membrane of Betz cells in both control and TDP-43 cases. Nuclear membranes of Betz cells in normal controls were almost perfect circle and no defects were observed (Fig.…”

“…TDP-43 directly regulates RanGap1 and depletion of TDP-43 results in downregulation of RanGap1 [71]. Transportin 1 does not directly bind to TDP-43 [45] but TDP-43 aggregates sequester Transportin 1 in the cytoplasm of cortical neurons contributing to nucleo-cytoplasmic transport defects [13]. It has also been suggested that depletion of TDP-43 results in elevated levels of Transportin 1 [63].…”

C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies

“…iPSC-derived neurons from patients with C9orf72 -ALS show evidence of nucleocytoplasmic defects, with decreased nuclear/cytoplasmic Ran ratio [170] and decreased nuclear RCC1/RanGEF [60], as well as large RanGAP1-positive puncta that occasionally co-localize with RNA foci [170]. In addition, TDP-43 inclusions in HeLa cells may sequester proteins involved in nucleocytoplasmic transport [17], and knockdown of TDP-43 in cell models leads to altered expression of a large group of proteins regulated by TDP-43, including nucleocytoplasmic transport proteins [112, 136]. …”