Abstract
The deposition of tau aggregates throughout the brain is a pathological characteristic within a group of neurodegenerative diseases collectively termed tauopathies, which includes Alzheimer’s disease. While recent findings suggest the involvement of unconventional secretory pathways driving tau into the extracellular space and mediating the propagation of the disease-associated pathology, many of the mechanistic details governing this process remain elusive. In the current study, we provide an in-depth characterization of the unconventional secretory pathway of tau and identify novel molecular determinants that are required for this process. Here, using Drosophila models of tauopathy, we correlate the hyperphosphorylation and aggregation state of tau with the disease-related neurotoxicity. These newly established systems recapitulate all the previously identified hallmarks of tau secretion, including the contribution of tau hyperphosphorylation as well as the requirement for PI(4,5)P2 triggering the direct translocation of tau. Using a series of cellular assays, we demonstrate that both the sulfated proteoglycans on the cell surface and the correct orientation of the protein at the inner plasma membrane leaflet are critical determinants of this process. Finally, we identify two cysteine residues within the microtubule binding repeat domain as novel cis-elements that are important for both unconventional secretion and trans-cellular propagation of tau.
Highlights
The deposition of tau aggregates throughout the brain is a pathological characteristic within a group of neurodegenerative diseases collectively termed tauopathies, which includes Alzheimer’s disease
The translocation process is completed by sulfated proteoglycans (PGs) on the outer cell surface, which act as anchor points that retain the majority of the extracellular tau p opulation[16,26]
The expression of human tau leads to a robust reduction in the lifespan of Drosophila melanogaster, which is further exacerbated by disease-associated m utations[38,39]
Summary
The deposition of tau aggregates throughout the brain is a pathological characteristic within a group of neurodegenerative diseases collectively termed tauopathies, which includes Alzheimer’s disease. We and others have demonstrated that the release of tau molecules from cells occurs via active cellular mechanisms that significantly impact the propagation of pathological conformations[16,17,18] This set of protein externalization mechanisms are collectively termed Unconventional Protein Secretion (UPS) and the common feature within proteins following such routes is that their export to the exterior does not rely on the classical secretory pathway[19]. Evidence for unconventional secretion of tau through a Type I UPS pathway has been reported[16,17], a mechanism that is based on direct protein translocation across the plasma m embrane[19,24] The translocation process is completed by sulfated proteoglycans (PGs) on the outer cell surface, which act as anchor points that retain the majority of the extracellular tau p opulation[16,26]
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