Retromer deficiency in Tauopathy models enhances the truncation and toxicity of Tau

Jamshid Asadzadeh, Evelyne Ruchti, Wei Jiao, Greta Limoni, Catherine MacLachlan, Scott A. Small, Graham Knott, Ismael Santa-Maria and Brian D. McCabe ()
Additional contact information
Jamshid Asadzadeh: EPFL – Swiss Federal Institute of Technology Lausanne
Evelyne Ruchti: EPFL – Swiss Federal Institute of Technology Lausanne
Wei Jiao: EPFL – Swiss Federal Institute of Technology Lausanne
Greta Limoni: EPFL – Swiss Federal Institute of Technology Lausanne
Catherine MacLachlan: BioEM Facility, EPFL – Swiss Federal Institute of Technology Lausanne
Scott A. Small: Columbia University
Graham Knott: EPFL – Swiss Federal Institute of Technology Lausanne
Ismael Santa-Maria: Columbia University
Brian D. McCabe: EPFL – Swiss Federal Institute of Technology Lausanne

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-32683-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32683-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-32683-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().