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Acta Neuropathol. 2019 Jan;137(1):47-69. doi: 10.1007/s00401-018-1934-8. Epub 2018 Nov 19.

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

Author information

1
Davee Department of Neurology and Clinical Neurological Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
2
Les Turner ALS Research and Patient Center, Chicago, IL, USA.
3
Department of Pathology, Northwestern University, Chicago, IL, USA.
4
Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
5
Davee Department of Neurology and Clinical Neurological Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. ozdinler@northwestern.edu.
6
Les Turner ALS Research and Patient Center, Chicago, IL, USA. ozdinler@northwestern.edu.
7
Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. ozdinler@northwestern.edu.
8
Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 303 E Chicago Ave., Ward 10-015, Chicago, IL, 60611, USA. ozdinler@northwestern.edu.

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; Betz cells; CSMN; Selective vulnerability

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