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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 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.

SUBMITTER: Chou CC

PROVIDER: S-EPMC5800968 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Chou Ching-Chieh CC Zhang Yi Y Umoh Mfon E ME Vaughan Spencer W SW Lorenzini Ileana I Liu Feilin F Sayegh Melissa M Donlin-Asp Paul G PG Chen Yu Han YH Duong Duc M DM Seyfried Nicholas T NT Powers Maureen A MA Kukar Thomas T Hales Chadwick M CM Gearing Marla M Cairns Nigel J NJ Boylan Kevin B KB Dickson Dennis W DW Rademakers Rosa R Zhang Yong-Jie YJ Petrucelli Leonard L Sattler Rita R Zarnescu Daniela C DC Glass Jonathan D JD Rossoll Wilfried W

Nature neuroscience 20180108 2

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 ...[more]

PMID: 29311743

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Project description:BackgroundTDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). So far, there is no therapy available for these neurodegenerative diseases. In addition, the impact of TDP-43 proteinopathy on neuronal translational profile also remains unknown.MethodsBiochemical, immunohistology and assay-based studies were done with cell cultures and transgenic mice models. We also used Ribotag with microarray and proteomic analysis to determine the neuronal translational profile in the mice model of ALS/FTD.ResultsHere, we report that oral administration of a novel analog (IMS-088) of withaferin-A, an antagonist of nuclear factor kappa-B (NF-ĸB) essential modulator (NEMO), induced autophagy and reduced TDP-43 proteinopathy in the brain and spinal cord of transgenic mice expressing human TDP-43 mutants, models of ALS/FTD. Treatment with IMS-088 ameliorated cognitive impairment, reduced gliosis in the brain of ALS/FTD mouse models. With the Ribotrap method, we investigated the impact of TDP-43 proteinopathy and IMS-088 treatment on the translation profile of neurons of one-year old hTDP-43A315T mice. TDP-43 proteinopathy caused translational dysregulation of specific mRNAs including translational suppression of neurofilament mRNAs resulting in 3 to 4-fold decrease in levels type IV neurofilament proteins. Oral administration of IMS-088 rescued the translational defects associated with TDP-43 proteinopathy and restored the synthesis of neurofilament proteins, which are essential for axon integrity and synaptic function.ConclusionsOur study revealed that induction of autophagy reduces TDP-43 pathology and ameliorates the translational defect seen in mice models of ALS/FTD. Based on these results, we suggest IMS-088 and perhaps other inducers of autophagy should be considered as potential therapeutics for neurodegenerative disorders with TDP-43 proteinopathies.

Dataset Information

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

Publications

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

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