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Divergent Phenotypes in Mutant TDP-43 Transgenic Mice Highlight Potential Confounds in TDP-43 Transgenic Modeling
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Details:
  • Pubmed ID:
    24466128
  • Pubmed Central ID:
    PMC3899264
  • Description:
    The majority of cases of frontotemporal lobar degeneration and amyotrophic lateral sclerosis are pathologically defined by the cleavage, cytoplasmic redistribution and aggregation of TAR DNA binding protein of 43 kDa (TDP-43). To examine the contribution of these potentially toxic mechanisms in vivo, we generated transgenic mice expressing human TDP-43 containing the familial amyotrophic lateral sclerosis-linked M337V mutation and identified two lines that developed neurological phenotypes of differing severity and progression. The first developed a rapid cortical neurodegenerative phenotype in the early postnatal period, characterized by fragmentation of TDP-43 and loss of endogenous murine Tdp-43, but entirely lacking aggregates of ubiquitin or TDP-43. A second, low expressing line was aged to 25 months without a severe neurodegenerative phenotype, despite a 30% loss of mouse Tdp-43 and accumulation of lower molecular weight TDP-43 species. Furthermore, TDP-43 fragments generated during neurodegeneration were not C-terminal, but rather were derived from a central portion of human TDP-43. Thus we find that aggregation is not required for cell loss, loss of murine Tdp-43 is not necessarily sufficient in order to develop a severe neurodegenerative phenotype and lower molecular weight TDP-43 positive species in mouse models should not be inherently assumed to be representative of human disease. Our findings are significant for the interpretation of other transgenic studies of TDP-43 proteinopathy.

  • Document Type:
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  • Funding:
    5R21NS071097-02/NS/NINDS NIH HHS/United States
    P01-AG17216-08/AG/NIA NIH HHS/United States
    P50AG16574/AG/NIA NIH HHS/United States
    PR080354/PR/OCPHP CDC HHS/United States
    R01 AG026251/AG/NIA NIH HHS/United States
    R01 NS 063964-01/NS/NINDS NIH HHS/United States
    R01AG026251/AG/NIA NIH HHS/United States
    R01AG026251-03A2/AG/NIA NIH HHS/United States
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