Taken together, our data supports that TDP-43 SUMOylation plays a protective role in mediating TDP-43 proteostasis in the CNS and that its blockade may confer a risk for ALS/FTD-like pathogenesis in an age-dependent, and sex-specific manner providing insights into molecular substrates underlying sexually dimorphic clinical features of ALS and FTD. This evidence concerns the gene TARDBP and frontotemporal dementia.