TARDBP and amyotrophic lateral sclerosis: This scenario can be mimicked in an experimental setting by overexpressing the mutant allele, which is expected to consequently inhibit the endogenous wild-type protein.31 In the period immediately following the discovery of TDP-43 as a neuropathological component of ALS, studies were focused on gain-of-function models, providing evidence that upregulation of both the mutant and the wild-type allele can cause neurodegeneration (for an extensive review see32).