Using a combination of molecular, cellular, and transcriptomic readouts combined with in vivo behavioral assays, we provide evidence that aberrant TDP-43K145Q recapitulates key hallmarks of TDP-43 proteinopathies, including altered TDP-43 solubility and localization, impaired autoregulation, and abnormal splicing function. The gene discussed is TARDBP; the disease is proteostasis deficiencies.