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

35 Citations (Scopus)

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 2012

Fingerprint

Frontotemporal Dementia
TDP-43 Proteinopathies
Prosencephalon
Ubiquitin
Transgenic Mice
Frontotemporal Lobar Degeneration
Neurons
Inclusion Bodies
DNA-Binding Proteins
Knockout Mice
Phenotype
Brain

Keywords

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

ASJC Scopus subject areas

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

Cite this

Cannon, A., Yang, B., Knight, J., Farnham, I. M., Zhang, Y., Wuertzer, C. A., ... 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

Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction. / Cannon, Ashley; Yang, Baoli; Knight, Joshua; Farnham, Ian M.; Zhang, Yongjie; Wuertzer, Charles A.; D'Alton, Simon; Lin, Wen Lang; Castanedes-Casey, Monica; Rousseau, Linda; Scott, Brittany; Jurasic, Michael; Howard, John; Yu, Xin; Bailey, Rachel; Sarkisian, Matthew R.; Dickson, Dennis W; Petrucelli, Leonard; Lewis, Jada.

In: Acta Neuropathologica, Vol. 123, No. 6, 06.2012, p. 807-823.

Research output: Contribution to journalArticle

Cannon, A, Yang, B, Knight, J, Farnham, IM, Zhang, Y, Wuertzer, CA, D'Alton, S, Lin, WL, Castanedes-Casey, M, Rousseau, L, Scott, B, Jurasic, M, Howard, J, Yu, X, Bailey, R, Sarkisian, MR, Dickson, DW, Petrucelli, L & Lewis, J 2012, 'Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction', Acta Neuropathologica, vol. 123, no. 6, pp. 807-823. https://doi.org/10.1007/s00401-012-0979-3
Cannon, Ashley ; Yang, Baoli ; Knight, Joshua ; Farnham, Ian M. ; Zhang, Yongjie ; Wuertzer, Charles A. ; D'Alton, Simon ; Lin, Wen Lang ; Castanedes-Casey, Monica ; Rousseau, Linda ; Scott, Brittany ; Jurasic, Michael ; Howard, John ; Yu, Xin ; Bailey, Rachel ; Sarkisian, Matthew R. ; Dickson, Dennis W ; Petrucelli, Leonard ; Lewis, Jada. / Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction. In: Acta Neuropathologica. 2012 ; Vol. 123, No. 6. pp. 807-823.
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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.",
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AU - Yang, Baoli

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AU - Wuertzer, Charles A.

AU - D'Alton, Simon

AU - Lin, Wen Lang

AU - Castanedes-Casey, Monica

AU - Rousseau, Linda

AU - Scott, Brittany

AU - Jurasic, Michael

AU - Howard, John

AU - Yu, Xin

AU - Bailey, Rachel

AU - Sarkisian, Matthew R.

AU - Dickson, Dennis W

AU - Petrucelli, Leonard

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