Non-genetically modified models exhibit TARDBP mRNA increase due to perturbed TDP-43 autoregulation

Abstract 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 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 TARDBPmRNA. To investigate the influence of autoregulationdysfunction , we inhibited the splicing of cryptic intron 6 using antisense oligonucleotides in vivo . This inhibition doubled the TardbpmRNA 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 TARDBPmRNA and decreased nuclear TDP-43. These non-genetically modified models exhibiting rise in the TARDBPmRNA levels suggest that TDP-43 autoregulationturbulence might be linked to the pathogenesis of ALS.