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01-01-2019 | Original Paper

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

Authors: Mukesh Gautam, Javier H. Jara, Nuran Kocak, Lauren E. Rylaarsdam, Ki Dong Kim, Eileen H. Bigio, P. Hande Özdinler

Published in: Acta Neuropathologica | Issue 1/2019

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-43^A315T-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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Title: Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology
Authors: Mukesh Gautam
Javier H. Jara
Nuran Kocak
Lauren E. Rylaarsdam
Ki Dong Kim
Eileen H. Bigio
P. Hande Özdinler
Publication date: 01-01-2019
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 1/2019
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-018-1934-8

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

At a glance: The ONWARDS insulin icodec trials

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Abstract

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