Abstract
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-43A315T mice) using a tetracycline-controlled inducible promotor system. Constitutive expression of transgenic TDP-43A315T in the absence of doxycycline resulted in pronounced early-onset and progressive neurodegeneration, and motor and memory deficits. Here, delayed transgene expression of TDP-43A315T by oral doxycycline treatment of iTDP-43A315T mice from birth till weaning was analyzed. After doxycycline withdrawal, transgenic TDP-43A315T 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-43A315T mice. Surprisingly, in contrast to the constitutive iTDP-43A315T mice, these mice did not develop astrogliosis. In summary, delayed activation coupled with gradual increase in TDP-43A315T 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-43A315T expression in mature mice.