Tunicamycin produces TDP-43 cytoplasmic inclusions in cultured brain organotypic slices

Cadman Leggett, Daniel S. McGehee, James Mastrianni, Wenbin Yang, Tao Bai, James R. Brorson

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

The cellular distribution of TAR DNA binding protein (TDP-43) is disrupted in several neurodegenerative disorders, including frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U subtype) and amyotrophic lateral sclerosis (ALS). In these conditions, TDP-43 is found in neuronal cytoplasmic inclusions, with loss of the normal nuclear expression. The mechanisms leading to TDP-43 redistribution and its role in disease pathophysiology remain unknown. We describe an in vitro neural tissue model that reproduces TDP-43 relocalization and inclusion formation. Two week-old coronal organotypic mouse brain slice cultures were treated with tunicamycin for 7 days. In cortical regions of treated slice cultures, cytoplasmic inclusions of TDP-43 immunoreactivity were observed, with loss of nuclear TDP-43 immunoreactivity. These inclusions were found in both astrocytes and neurons, and were of both skein-like and round morphologies. In contrast, TDP-43 cytoplasmic inclusions were not found in slices treated with staurosporine to induce apoptosis, or with trans-4-carboxy-l-proline (PDC) to induce chronic glutamate excitotoxicity. Furthermore, TDP-43 cytoplasmic inclusions did not co-localize with cleaved caspase-3, suggesting that TDP-43 mislocalization does not generally accompany caspase activation or apoptosis. The induction of TDP-43 cytoplasmic translocation in cerebrocortical slice cultures by tunicamycin provides a platform for further mechanistic investigations of pathological processing of TDP-43.

Original languageEnglish (US)
Pages (from-to)66-73
Number of pages8
JournalJournal of the neurological sciences
Volume317
Issue number1-2
DOIs
StatePublished - Jun 15 2012

Keywords

  • Amyotrophic lateral sclerosis
  • Apoptosis
  • Caspase-3
  • Frontotemporal lobar degeneration
  • Inclusions
  • Tunicamycin

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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