Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction

Ashley Cannon, Baoli Yang, Joshua Knight, Ian M. Farnham, Yongjie Zhang, Charles A. Wuertzer, Simon D'Alton, Wen Lang Lin, Monica Castanedes-Casey, Linda Rousseau, Brittany Scott, Michael Jurasic, John Howard, Xin Yu, Rachel Bailey, Matthew R. Sarkisian, Dennis W. Dickson, Leonard Petrucelli, Jada Lewis

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Ubiquitin-immunoreactive neuronal inclusions composed of TAR DNA binding protein of 43 kDa (TDP-43) are a major pathological feature of frontotemporal lobar degeneration (FTLD-TDP). In vivo studies with TDP-43 knockout mice have suggested that TDP-43 plays a critical, although undefined role in development. In the current report, we generated transgenic mice that conditionally express wild-type human TDP-43 (hTDP-43) in the fore-brain and established a paradigm to examine the sensitivity of neurons to TDP-43 overexpression at different developmental stages. Continuous TDP-43 expression during early neuronal development produced a complex phenotype, including aggregation of phospho-TDP-43, increased ubiquitin immunoreactivity, mitochondrial abnormalities, neurodegeneration and early lethality. In contrast, later induction of hTDP-43 in the forebrain of weaned mice prevented early death and mitochondrial abnormalities while yielding salient features of FTLD-TDP, including progressive neurodegeneration and ubiquitinated, phospho-TDP-43 neuronal cytoplasmic inclusions. These results suggest that neurons in the developing forebrain are extremely sensitive to TDP-43 overexpression and that timing of TDP-43 over-expression in transgenic mice must be considered when distinguishing normal roles of TDP-43, particularly as they relate to development, from its pathogenic role in FTLD-TDP and other TDP-43 proteinopathies. Finally, our adult induction of hTDP-43 strategy provides a mouse model that develops critical pathological features that are directly relevant for human TDP-43 proteinopathies.

Original languageEnglish (US)
Pages (from-to)807-823
Number of pages17
JournalActa neuropathologica
Volume123
Issue number6
DOIs
StatePublished - Jun 1 2012

Keywords

  • Amyotrophic lateral sclerosis
  • Apoptosis
  • Frontotemporal lobar degeneration
  • Neurodevelopment
  • TDP-43
  • Transgenic mice

ASJC Scopus subject areas

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

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    Cannon, A., Yang, B., Knight, J., Farnham, I. M., Zhang, Y., Wuertzer, C. A., D'Alton, S., Lin, W. L., Castanedes-Casey, M., Rousseau, L., Scott, B., Jurasic, M., Howard, J., Yu, X., Bailey, R., Sarkisian, M. R., Dickson, D. W., Petrucelli, L., & Lewis, J. (2012). Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction. Acta neuropathologica, 123(6), 807-823. https://doi.org/10.1007/s00401-012-0979-3