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 Özdinler*

*Corresponding author for this work

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)47-69
Number of pages23
JournalActa Neuropathologica
Volume137
Issue number1
DOIs
StatePublished - Jan 21 2019

Keywords

  • ALS
  • Betz cells
  • CSMN
  • Selective vulnerability

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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