Progressive motor weakness in transgenic mice expressing human TDP-43

Nancy R. Stallings, Krishna Puttaparthi, Christina M. Luther, Dennis K. Burns, Jeffrey L. Elliott

Research output: Contribution to journalArticle

124 Scopus citations

Abstract

Familial ALS patients with TDP-43 gene mutations and sporadic ALS patients share common TDP-43 neuronal pathology. To delineate mechanisms underlying TDP-43 proteinopathies, transgenic mice expressing A315T, M337V or wild type human TDP-43 were generated. Multiple TDP-43 founders developed a severe early motor phenotype that correlated with TDP-43 levels in spinal cord. Three A315T TDP-43 lines developed later onset paralysis with cytoplasmic ubiquitin inclusions, gliosis and TDP-43 redistribution and fragmentation. The WT TDP-43 mouse line with highest spinal cord expression levels remains asymptomatic, although these mice show spinal cord pathology. One WT TDP-43 line with high skeletal muscle levels of TDP-43 developed a severe progressive myopathy. Over-expression of TDP-43 in vivo is sufficient to produce progressive motor phenotypes by a toxic gain of function paradigm. Transgenic mouse lines expressing untagged mutant and wild type TDP-43 under the same promoter represent a powerful new model system for studying TDP-43 proteinopathies in vivo.

Original languageEnglish (US)
Pages (from-to)404-414
Number of pages11
JournalNeurobiology of Disease
Volume40
Issue number2
DOIs
StatePublished - Nov 1 2010

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Keywords

  • ALS
  • Inclusions
  • Motor neuron
  • Myopathy
  • Neurodegeneration
  • TDP-43

ASJC Scopus subject areas

  • Neurology

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