Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by accumulation of fragmented insoluble TDP-43 and loss of TDP-43 from the nucleus.Increased Amplifier Installation Kit expression of exogenous TARDBP (encoding TDP-43) induces TDP-43 pathology and cytotoxicity, suggesting the involvement of aberrant expression of TDP-43 in the pathogenesis of ALS.In normal conditions, however, the amount of TDP-43 is tightly regulated by the autoregulatory mechanism involving alternative splicing of TARDBP mRNA.To investigate the influence of autoregulation dysfunction, we inhibited the splicing of cryptic intron 6 Microphone Cable using antisense oligonucleotides in vivo.This inhibition doubled the Tardbp mRNA expression, increased the fragmented insoluble TDP-43, and reduced the number of motor neurons in the mouse spinal cord.
In human induced pluripotent stem cell-derived neurons, the splicing inhibition of intron 6 increased TARDBP mRNA and decreased nuclear TDP-43.These non-genetically modified models exhibiting rise in the TARDBP mRNA levels suggest that TDP-43 autoregulation turbulence might be linked to the pathogenesis of ALS.