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Author Notes:

Correspondence should be addressed to W.R. (Rossoll.Wilfried@mayo.edu)

These authors contributed equally to this work.

W.R. conceived and directed the project. C-C.C., Y.Z. and W.R. designed the experiments. C-C.C. and W.R. interpreted data and wrote the manuscript.

C-C.C. and W.R. interpreted data and wrote the manuscript. C-C.C. characterized protein interactome, performed bioinformatic analysis and conducted experiments in N2a cells, primary cortical neurons and human fibroblasts with help from F.L. and Y.H.C.. Y.Z. performed the BioID pulldown and sample preparation for LC-MS/MS analysis.

M.E.U. performed immunohistochemistry staining. S.W.V., M.S. and D.C.Z. performed Drosophila experiments. I.L. and R.S. performed experiments in iPSC-derived motor neurons.

C-C.C. and P.G.D. conducted SIM experiments. D.M.D., N.T.S. and M.A.P. provided technical support.

T.K. provided key reagents. C.M.H., M.G., N.J.C., K.B.B., D.W.D., R.R., Y-J.Z., L.P. and J.D.G. provided patient tissue with associated clinical and genetics data.

We thank Kathryn R. Moss and Kristen T. Thomas for help with the preparation of primary cortical neurons, Gary J. Bassell for logistical support, and Monica Castanedes-Casey for expert staining of human brain tissue.

For numerous expression plasmids used in this study (Supplementary Table 3), we thank Martin Hetzer, Jan Ellenberg, Valérie Doye, Jose Teodoro and Jomon Joseph, Larry Gerace, Bryce Paschal, and Mary Dasso.

We thank the Bloomington Drosophila Stock Center for fly lines, and Emory Integrated Proteomics Core, Neuropathology/ Histochemistry Core and Robert P. Apkarian Integrated Electron Microscopy Core for technical support.

The authors declare no competing financial interests.

Subjects:

Research Funding:

This work was supported by grants from the ALS Association (17-IIP-353) to W.R., and (16-IIP-278) to R.S., the Emory Medicine Catalyst Funding Program to W.R., Muscular Dystrophy Association (MDA348086) to R.S., and NIH grants K08-NS087121 to C.M.H., P30-NS055077 to the Neuropathology/Histochemistry core of the Emory NINDS Neurosciences Core Facility, AG025688 to Emory’s Alzheimer’s Disease Research Center, NIH R01-NS091299 to D.C.Z., R35-NS097261 to R.R., R01-NS085207 to R.S., R01NS091749 to W.R., R01-NS093362 to W.R. and T.K., who is also supported by The Bluefield Project to Cure FTD, the Alzheimer’s Drug Discovery Foundation to N.J.C, and NIH R01-AG053960 to N.T.S., who is also supported in part by an Alzheimer’s Association (ALZ), Alzheimer’s Research UK (ARUK), The Michael J. Fox Foundation for Parkinson’s Research (MJFF), and the Weston Brain Institute Biomarkers Across Neurodegenerative Diseases Grant (11060).

S.V. was partially funded by UBRP with funds from the UA Provost’s Office. P.G.D. was funded by an ARCS Fellowship Roche Foundation Award.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • AMYOTROPHIC-LATERAL-SCLEROSIS
  • FRONTOTEMPORAL LOBAR DEGENERATION
  • MOTOR-NEURON DISEASE
  • RNA-BINDING PROTEIN
  • MESSENGER-RNA
  • DROSOPHILA MODEL
  • REPEAT EXPANSION
  • A315T MUTATION
  • ALS
  • EXPRESSION

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

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Journal Title:

Nature Neuroscience

Volume:

Volume 21, Number 2

Publisher:

, Pages 228-239

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2017 The Author(s).

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