In conclusion we have shown, using bacterial IBs containing aggregated TDP-43 as a model system, that both FL and Ct TDP-43 aggregates consist of non-amyloid assemblies that have an intrinsically high ability to cause neuronal dysfunction when delivered into the cytoplasm, contributing to elucidate the pathogenesis of TDP-43 proteinopathies such as FTLD-U and ALS. Here, TARDBP is linked to proteostasis deficiencies.