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

J Neurol Sci. 2012 Jun 15;317(1-2):66-73. doi: 10.1016/j.jns.2012.02.027. Epub 2012 Mar 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / toxicity
  • Brain / metabolism*
  • Brain / pathology
  • DNA-Binding Proteins / biosynthesis*
  • Inclusion Bodies / metabolism*
  • Inclusion Bodies / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Organ Culture Techniques
  • Protein Transport / physiology
  • TDP-43 Proteinopathies / chemically induced
  • TDP-43 Proteinopathies / metabolism
  • TDP-43 Proteinopathies / pathology
  • Tunicamycin / pharmacology*
  • Tunicamycin / toxicity


  • Anti-Bacterial Agents
  • DNA-Binding Proteins
  • Tunicamycin