TARDBP and proteostasis deficiencies: More specifically, we show that RfxCas13d and a high-fidelity version of it can be used to inhibit the formation of TDP-43+ aggregates in cell culture models of the pathology and that the in vivo delivery of an ataxin-2-targeting RfxCas13d-based system to a mouse model of a TDP-43 proteinopathy can provide broad therapeutic benefit.