All roads lead to TDP43: Convergent mechanisms of TDP43 autoregulation.

TDP43 is an essential RNA-binding protein with fundamental ties to neurodegenerative disorders. In this issue, Hasegawa-Ogawa and colleagues (https://doi.org/10.1083/jcb.202406097) describe a new mechanism for regulating TDP43 function, involving alternatively spliced variants that inhibit TDP43 via dominant-negative activity.