Numb reduces Tau levels and prevents neurodegeneration in mouse models of tauopathy in an isoform-specific manner

Accumulation of the microtubule-associated protein Tau is linked to neuronal cell death in tauopathies, but how exactly intraneuronal Tau levels are regulated in health and disease remains unclear. Here we identify the trafficking adaptor protein Numb as an essential regulator of Tau homeostasis. Conditional inactivation of Numb in retinal ganglion cells (RGCs) increases monomeric and oligomeric Tau levels, leading to axonal blebbing followed by neuronal cell loss in aged mice. Moreover, in a mouse model of tauopathy, inactivation of Numb in RGCs and spinal motoneurons accelerates neurodegeneration, and leads to precocious hindlimb paralysis. Conversely, overexpression of the long isoform of Numb (Numb-72), but not other isoforms, decreases intracellular Tau levels by promoting the extracellular release of monomeric Tau, and AAV-mediated delivery of Numb-72 in RGCs in vivo prevents neurodegeneration in two different mouse models of tauopathy. Taken together, these results uncover Numb as a modulator of intracellular Tau levels and identify Numb-72 as a novel therapeutic factor for tauopathies.