Retromer deficiency in Tauopathy models enhances the truncation and toxicity of Tau.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
27 08 2022
27 08 2022
Historique:
received:
07
05
2018
accepted:
10
08
2022
entrez:
27
8
2022
pubmed:
28
8
2022
medline:
31
8
2022
Statut:
epublish
Résumé
Alteration of the levels, localization or post-translational processing of the microtubule associated protein Tau is associated with many neurodegenerative disorders. Here we develop adult-onset models for human Tau (hTau) toxicity in Drosophila that enable age-dependent quantitative measurement of central nervous system synapse loss and axonal degeneration, in addition to effects upon lifespan, to facilitate evaluation of factors that may contribute to Tau-dependent neurodegeneration. Using these models, we interrogate the interaction of hTau with the retromer complex, an evolutionarily conserved cargo-sorting protein assembly, whose reduced activity has been associated with both Parkinson's and late onset Alzheimer's disease. We reveal that reduction of retromer activity induces a potent enhancement of hTau toxicity upon synapse loss, axon retraction and lifespan through a specific increase in the production of a C-terminal truncated isoform of hTau. Our data establish a molecular and subcellular mechanism necessary and sufficient for the depletion of retromer activity to exacerbate Tau-dependent neurodegeneration.
Identifiants
pubmed: 36030267
doi: 10.1038/s41467-022-32683-5
pii: 10.1038/s41467-022-32683-5
pmc: PMC9420134
doi:
Substances chimiques
tau Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5049Subventions
Organisme : NIH HHS
ID : P40 OD018537
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS095922
Pays : United States
Informations de copyright
© 2022. The Author(s).
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