Temporal Expression of Mutant TDP-43 Correlates with Early Amyotrophic Lateral Sclerosis Phenotype and Motor Weakness

Abstract

BACKGROUND Mutant transactive response DNA-binding protein (TDP-43) is closely correlated to inherited form of amyotrophic lateral sclerosis (ALS). TDP-43 transgenic rats can reproduce the core phenotype of ALS and constitutive expression of TDP-43 caused postnatal death. OBJECTIVE To understand whether neurologic deficiency caused by mutant TDP-43 is dependent on its temporal expression. METHOD Transgenic rats were established that express mutant human TDP-43 (M337V substitution) in neurons, then a Tet-off system was used to regulate its expression. RESULTS TDP-43 mutant transgenic rats developed remarkable weakness after the transgene was activated. Rats with expression of mutant TDP-43 at 30 days showed a more aggressive phenotype. More severe pathological changes of neurogenic atrophy were observed in these rats. CONCLUSION Temporal expression of mutant TDP-43 in neurons promotes serious phenotype in rats. The dysfunction of TDP-43 impacts profoundly on the development of motor neurons and skeletal muscles.