In conclusion, we show here that RNA-targeting CRISPR effector proteins can be programmed to target ataxin-2, a potent modifier of TDP-43-associated toxicity, and that the in vivo delivery of an ataxin-2-targeting Cas13 system to a mouse model of TDP-43 proteinopathy could provide broad therapeutic benefit. The gene discussed is TARDBP; the disease is proteostasis deficiencies.