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

Asadzadeh, Jamshid, Ruchti, Evelyne, Jiao, Wei, Limoni, Greta, MacLachlan, Catherine, Small, Scott A., Knott, Graham, Santa-Maria, Ismael, McCabe, Brian D.·2022·Nature Communications
DOI 10.1038/s41467-022-32683-5PMC PMC9420134
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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.

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  • Both SNX17-Retriever and SNX27-Retromer pathways are crucial for maintaining excitatory synapse function.

    “Despite their independent cargo profiles and molecular machinery, both SNX17-Retriever and SNX27-Retromer pathways are crucial for maintaining excitatory synapse function”

    From Dual endomembrane recycling pathways function in parallel to support synapse maintenance and plasticity (2025) · cites this paper as Asadzadeh et al., 2022

    The Introduction (page unavailable) reports that reducing retromer activity can inhibit long-term potentiation at hippocampal synapses, supporting a general link between retromer and synaptic function. Neither that passage nor the searched passages address SNX17-Retriever or SNX27-Retromer specifically, their independent cargo profiles, or whether both pathways are crucial for excitatory synapse function. (LLM, conf=0.82)

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Metadata

Authors
Asadzadeh, J., Ruchti, E., Jiao, W., Limoni, G., MacLachlan, C., Small, S. A., Knott, G., Santa-Maria, I., & McCabe, B. D.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-08-27
Volume
13
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-022-32683-5
PMC
PMC9420134
Cited by
14
References
10
Language
en
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