Progressive motor weakness in transgenic mice expressing human TDP-43.
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.
Stallings
Nancy R
NR
Department of Neurology, University of Texas, Southwestern Medical Center, Dallas, TX 75390, USA.
Puttaparthi
Krishna
K
Luther
Christina M
CM
Burns
Dennis K
DK
Elliott
Jeffrey L
JL
D000818:Animals; D015153:Blotting, Western; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D016472:Motor Neuron Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D018908:Muscle Weakness / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D057177:TDP-43 Proteinopathies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology
D018076:DNA, Complementary; D004268:DNA-Binding Proteins