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  Interplay of pathogenic forms of human tau with different autophagic pathways

Caballero, B., Wang, Y., Diaz, A., Tasset, I., Juste, Y. R., Stiller, B., et al. (2018). Interplay of pathogenic forms of human tau with different autophagic pathways. Aging Cell, 17(1): e12692. doi:10.1111/acel.12692.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0001-7A6B-F Version Permalink: http://hdl.handle.net/21.11116/0000-0007-50E1-0
Genre: Journal Article

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 Creators:
Caballero, Benjamin1, Author
Wang, Yipeng1, Author
Diaz, Antonio1, Author
Tasset, Inmaculada1, Author
Juste, Yves Robert1, Author
Stiller, Barbara1, Author
Mandelkow, Eckhard2, Author              
Cuervo, Ana Maria1, Author
Mandelkow, Eva-Maria2, Author              
Affiliations:
1External Organizations, ou_persistent22              
2Neuronal Cytoskeleton and Alzheimer's Disease, Cooperations, Center of Advanced European Studies and Research (caesar), Max Planck Society, ou_2173677              

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 Abstract: Loss of neuronal proteostasis, a common feature of the aging brain, is accelerated in neurodegenerative disorders, including different types of tauopathies. Aberrant turnover of tau, a microtubule-stabilizing protein, contributes to its accumulation and subsequent toxicity in tauopathy patients' brains. A direct toxic effect of pathogenic forms of tau on the proteolytic systems that normally contribute to their turnover has been proposed. In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone-mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this age-related disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk-associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway. We also found defective autophagic degradation of tau when using mutations that mimic common posttranslational modifications in tau or known to promote its aggregation. Interestingly, although most mutations markedly reduced degradation of tau through autophagy, the step of this process preferentially affected varies depending on the type of tau mutation. Overall, our studies unveil a complex interplay between the multiple modifications of tau and selective forms of autophagy that may determine its physiological degradation and its faulty clearance in the disease context.

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 Dates: 2017-10-122018-02
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000422661300008
DOI: 10.1111/acel.12692
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Title: Aging Cell
Source Genre: Journal
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Publ. Info: Oxford, UK : Blackwell Pub.
Pages: - Volume / Issue: 17 (1) Sequence Number: e12692 Start / End Page: - Identifier: ISSN: 1474-9718
CoNE: https://pure.mpg.de/cone/journals/resource/110999122711006