TARDBP and proteostasis deficiencies: Biomarker evidence from pre-symptomatic stages of these diseases has been instrumental in reframing these traditional views, and here we present such evidence for ALS, i.e. evidence of pre-symptomatic disease-associated proteinopathy from a wide range of peripheral organ systems decades prior to motor symptoms, with skin TDP-43 pathology as a lead candidate biomarker for early detection of disease.