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

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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.

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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.

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Authors and Affiliations

  1. Davee Department of Neurology and Clinical Neurological Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Mukesh Gautam, Javier H. Jara, Nuran Kocak, Lauren E. Rylaarsdam, Ki Dong Kim & P. Hande Özdinler

  2. Les Turner ALS Research and Patient Center, Chicago, IL, USA

    Mukesh Gautam, Javier H. Jara, Nuran Kocak & P. Hande Özdinler

  3. Department of Pathology, Northwestern University, Chicago, IL, USA

    Eileen H. Bigio

  4. Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Eileen H. Bigio & P. Hande Özdinler

  5. Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 303 E Chicago Ave., Ward 10-015, Chicago, IL, 60611, USA

    P. Hande Özdinler

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  1. Mukesh Gautam
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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.

Corresponding author

Correspondence to P. Hande Özdinler.

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401_2018_1934_MOESM1_ESM.tif

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

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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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Gautam, M., Jara, J.H., Kocak, N. et al. Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology. Acta Neuropathol 137, 47–69 (2019). https://doi.org/10.1007/s00401-018-1934-8

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  • DOI: https://doi.org/10.1007/s00401-018-1934-8

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