Crucially, non-CNS pre-symptomatic TDP-43 pathologies have been shown in ALS by identifying toxic TDP-43 gain-of-function (28, 53, 54), or TDP-43 loss-of-function through splicing repression (55) prior to clinical symptoms, and sometimes over a decade before (28), indicating that early non-motor symptoms, and non-CNS tissues along with fluid biomarkers, provide potential for early diagnosis of ALS. The gene discussed is TARDBP; the disease is amyotrophic lateral sclerosis.