Divergent phenotypes in mutant TDP-43 transgenic mice highlight potential confounds in TDP-43 transgenic modeling.
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.
Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, Florida, United States of America ; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America.
Simon
S
D'Alton
Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, Florida, United States of America.
Marcelle
M
Altshuler
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America.
Ashley
A
Cannon
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America.
Dennis W
DW
Dickson
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America.
Leonard
L
Petrucelli
Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, Florida, United States of America ; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America.
Jada
J
Lewis
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D057177:TDP-43 Proteinopathies / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins