MAPT and neurodegenerative disease: Given the widely observed accumulation of neurotoxic proteins in extracellular milieu in animal models of neurodegenerative diseases and in patients, and that uptake of misfolded proteins such as Tau, α-Synuclein, and superoxide dismutase 1 (SOD1) has been suggested to contribute to the pathogenesis of neurodegenerative diseases [46], it is tempting to speculate that secretion through UPS, normally under tight regulation, may become deregulated and thus contribute to the pathological accumulation or transmission of misfolded proteins during disease progression [47].