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Acta Neuropathologica

, Volume 137, Issue 1, pp 47–69 | Cite as

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

  • Mukesh Gautam
  • Javier H. Jara
  • Nuran Kocak
  • Lauren E. Rylaarsdam
  • Ki Dong Kim
  • Eileen H. Bigio
  • P. Hande ÖzdinlerEmail author
Original Paper

Abstract

Insoluble aggregates containing TDP-43 are widely observed in the diseased brain, and defined as “TDP-43 pathology” in a spectrum of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease and ALS with frontotemporal dementia. Here we report that Betz cells of patients with TDP-43 pathology display a distinct set of intracellular defects especially at the site of nuclear membrane, mitochondria and endoplasmic reticulum (ER). Numerous TDP-43 mouse models have been generated to discern the cellular and molecular basis of the disease, but mechanisms of neuronal vulnerability remain unknown. In an effort to define the underlying causes of corticospinal motor neuron (CSMN) degeneration, we generated and characterized a novel CSMN reporter line with TDP-43 pathology, the prp-TDP-43A315T-UeGFP mice. We find that TDP-43 pathology related intracellular problems emerge very early in the disease. The Betz cells in humans and CSMN in mice both have impaired mitochondria, and display nuclear membrane and ER defects with respect to TDP-43 pathology.

Keywords

ALS CSMN Betz cells Selective vulnerability 

Notes

Acknowledgements

This work was supported by NIH (R21NS085750, R01 NS085161) and Les Turner ALS Foundation. We thank Dr. Marco Martina and Gabriella Sekerkova for help with EM analysis, and Megan Schultz for immunohistochemistry experiments. We thank Jayson Wilson for excellent help with preparing sections of postmortem human samples.

Author contributions

MG, JHJ, EHB, PHO designed the experiments. MG, JHJ, LER, NK, KDK conducted the experiments. MG, JHJ, EHB and PHO analyzed the data and wrote the manuscript.

Supplementary material

401_2018_1934_MOESM1_ESM.tif (1.4 mb)
Supplementary Fig. 1 A representative electron micrographic image taken in layer 5 of the motor cortex. Betz cells are distinguished by their pyramidal cell body, the large size of their nucleus and soma (black arrowhead). Non-Betz cells are much smaller in size (black arrow). Scale bar = 5 μm
401_2018_1934_MOESM2_ESM.tif (4.5 mb)
Supplementary Fig. 2 Betz cells of ALS patients with TDP-43 pathology that lack nucleocytoplasmic inclusions (NCIs) also display key ultrastructural defects. a, b Representative images of Betz cells (green) display low levels of TDP-43 (red, arrow) expression in the nucleus, without any accumulations in the cytoplasm or in the nucleus. Electron micrograph of a representative Betz cell with numerous autophagolysosomes in the cytoplasm (c). A close look reveal nuclear membrane defects (d, white arrow), presence autophagolysosomes (e, white arrows), swollen ER (f, white arrows), and disintegrating mitochondria (g, white arrow). Scale bar: a, b = 20 μm; c = 1 μm; d, e, f = 500 nm; g = 200 nm

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Davee Department of Neurology and Clinical Neurological SciencesNorthwestern University Feinberg School of MedicineChicagoUSA
  2. 2.Les Turner ALS Research and Patient CenterChicagoUSA
  3. 3.Department of PathologyNorthwestern UniversityChicagoUSA
  4. 4.Cognitive Neurology and Alzheimer’s Disease CenterNorthwestern University Feinberg School of MedicineChicagoUSA
  5. 5.Robert H. Lurie Comprehensive Cancer CenterNorthwestern UniversityChicagoUSA

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