| First Author | Chan G | Year | 2020 |
| Journal | Am J Pathol | Volume | 190 |
| Issue | 8 | Pages | 1713-1722 |
| PubMed ID | 32371051 | Mgi Jnum | J:294557 |
| Mgi Id | MGI:6452356 | Doi | 10.1016/j.ajpath.2020.04.009 |
| Citation | Chan G, et al. (2020) Neurodegeneration and Motor Deficits in the Absence of Astrogliosis upon Transgenic Mutant TDP-43 Expression in Mature Mice. Am J Pathol 190(8):1713-1722 |
| abstractText | Amyotrophic lateral sclerosis is a rapidly progressing and fatal disease characterized by muscular atrophy due to loss of upper and lower motor neurons. Pathogenic mutations in the TARDBP gene encoding TAR DNA binding protein-43 (TDP-43) have been identified in familial amyotrophic lateral sclerosis. We have previously reported transgenic mice with neuronal expression of human TDP-43 carrying the pathogenic A315T mutation (iTDP-43(A315T) mice) using a tetracycline-controlled inducible promotor system. Constitutive expression of transgenic TDP-43(A315T) in the absence of doxycycline resulted in pronounced early-onset and progressive neurodegeneration, and motor and memory deficits. Here, delayed transgene expression of TDP-43(A315T) by oral doxycycline treatment of iTDP-43(A315T) mice from birth till weaning was analyzed. After doxycycline withdrawal, transgenic TDP-43(A315T) expression gradually increased and resulted in cytoplasmic TDP-43, widespread ubiquitination, and cortical and hippocampal atrophy. In addition, these mice developed motor and gait deficits with underlying muscle atrophy, similar to that observed in the constitutive iTDP-43(A315T) mice. Surprisingly, in contrast to the constitutive iTDP-43(A315T) mice, these mice did not develop astrogliosis. In summary, delayed activation coupled with gradual increase in TDP-43(A315T) expression in the central nervous system of mature mice resulted in progressive functional deficits with neuron and muscle loss, but in the absence of a glial response. This suggests that astrocytosis does not contribute to functional deficits and neuronal loss upon TDP-43(A315T) expression in mature mice. |
