XVII Genetics Conference
Abstract
TDP-43 (encoded by the TARDBP gene) is an RNA-binding protein critical for the splicing of numerous transcripts and represents a central player in the pathogenesis of amyotrophic lateral sclerosis (ALS). A gain-of-function in TDP-43, which causes widespread splicing dysregulation, has been proposed as one of the triggering mechanisms of ALS. To investigate this further and to determine whether there is a relationship between splicing gain-of-function and motor neuron degeneration, we used two unique knock-in mouse models carrying point mutations in the endogenous Tardbp gene: TardbpQ331K and TardbpM323K.
We found that TardbpM323K/M323K mice exhibited progressive degeneration of spinal motor neurons—a phenotype not observed in TardbpQ331K/Q331K animals. Moreover, TardbpM323K/M323K mice displayed an age-dependent increase in TDP-43 splicing gain-of-function in the spinal cord, which was more pronounced than that seen in TardbpQ331K/Q331K mice. We also generated, for the first time, TardbpQ331K/M323K compound heterozygotes, which confirmed that the M323K mutation induces a greater splicing gain-of-function than the Q331K mutation in the spinal cord. Together, these findings suggest a spinal-cord–specific correlation between motor neuron degeneration and TDP-43 splicing gain-of-function.