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@ARTICLE{Katsinelos:169396,
author = {T. Katsinelos$^*$ and W. A. McEwan and T. Jahn$^*$ and W.
Nickel},
title = {{I}dentification of cis-acting determinants mediating the
unconventional secretion of tau.},
journal = {Scientific reports},
volume = {11},
number = {1},
issn = {2045-2322},
address = {[London]},
publisher = {Macmillan Publishers Limited, part of Springer Nature},
reportid = {DKFZ-2021-01470},
pages = {12946},
year = {2021},
note = {#EA:B180#},
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.},
cin = {B180},
ddc = {600},
cid = {I:(DE-He78)B180-20160331},
pnm = {312 - Funktionelle und strukturelle Genomforschung
(POF4-312)},
pid = {G:(DE-HGF)POF4-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:34155306},
pmc = {pmc:PMC8217235},
doi = {10.1038/s41598-021-92433-3},
url = {https://inrepo02.dkfz.de/record/169396},
}