These observations underscore the multifaceted role of TDP-43 in the endolysosomal pathway and has led to the hypothesis of a negative regulatory feedback loop underlying ALS/FTD as TDP-43 sequestration into aggregates leads to reduced functional TDP-43 levels, in turn leading to defective lysosomal degradation pathways, which in turn will aggravate the TDP-43 aggregation, eventually culminating in neurodegeneration [295]. The gene discussed is TARDBP; the disease is frontotemporal dementia.