The Cell Biology of Tau Secretion

Abstract

The progressive accumulation and spread of misfolded tau protein in the nervous system is the hallmark of tauopathies, progressive neurodegenerative diseases with only symptomatic treatments available. A growing body of evidence suggests that spreading of tau pathology can occur via cell-to-cell transfer involving secretion and internalization of pathological forms of tau protein followed by templated misfolding of normal tau in recipient cells. Several studies have addressed the cell biological mechanisms of tau secretion. It now appears that instead of a single mechanism, cells can secrete tau via three coexisting pathways: (1) translocation through the plasma membrane; (2) membranous organelles-based secretion; and (3) ectosomal shedding. The relative importance of these pathways in the secretion of normal and pathological tau is still elusive, though. Moreover, glial cells contribute to tau propagation, and the involvement of different cell types, as well as different secretion pathways, complicates the understanding of prion-like propagation of tauopathy. One of the important regulators of tau secretion in neuronal activity, but its mechanistic connection to tau secretion remains unclear and may involve all three secretion pathways of tau. This review article summarizes recent advancements in the field of tau secretion with an emphasis on cell biological aspects of the secretion process and discusses the role of neuronal activity and glial cells in the spread of pathological forms of tau.

Keywords: autophagy; extracellular vesicles; glial cells; lysosomes; membranous organelles-based secretion; synaptic transmission; tau; unconventional protein secretion.

Figure 1

Pathways involved in tau secretion. (1) Direct translocation through the plasma membrane involves the interaction of tau with specific lipids, such as PI(4,5)P₂ (not shown), at the inner leaflet of the plasma membrane and interaction with HSPGs at the outer leaflet of the plasma membrane that facilitates the release of tau to the extracellular space. (2) Exosomal secretion involves tau uptake into intraluminal vesicles (ILVs) of LE/Multivesicular bodies (MVBs) by their inward budding and subsequent release of these ILV (now termed exosomes) via fusion of LE/MVBs with the plasma membrane. (3) Autophagy-based secretion involves sequestration of tau by an expanding phagophore and fusion of the resulting autophagosome with the plasma membrane to release tau. Autophagosome may also first fuse with LE/MVB on its pathway to the plasma membrane. (4) LE/lysosome-mediated secretion (misfolding-associated protein secretion, MAPS) involves the capture of tau by USP19 at the ER membrane, subsequent translocation of tau into the lumen of closely contacting LE/lysosomes, facilitated by Hsc70 and its LE/Lys chaperone DNAJC5, and fusion of LE/lysosome with the plasma membrane to release vesicle-free tau. (5) Ectosomal secretion involves the budding of tau-containing extracellular vesicles directly from the plasma membrane to release tau inside vesicles, which are typically larger than exosomes and have different membrane compositions. AP, autophagosome; EE, early endosome; HSPG, heparan sulfate proteoglycans; LE, late endosome; MVB, multivesicular body.