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.
Highlights
Neurodegenerative diseases are incurable and disabling conditions characterized by progressive degeneration and loss of cells, structures, and functions of the nervous system
Many diseases that are predominantly sporadic with the multifactorial origin, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), have familial forms, typically indistinguishable from the sporadic diseases in their clinical manifestations and neuropathology (Lippa et al, 1996; Papapetropoulos et al, 2007)
An expanding phagophore may sequester cytosolic proteins, leading to the formation of an autophagosome, which fuses with the plasma membrane instead of a lysosome, releasing its content to the extracellular space (Claude-Taupin et al, 2017; Rabouille, 2017)
Summary
Neurodegenerative diseases are incurable and disabling conditions characterized by progressive degeneration and loss of cells, structures, and functions of the nervous system. (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. (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.
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