Interplay of pathogenic forms of human tau with different autophagic pathways

Benjamin Caballero, Yipeng Wang, Antonio Diaz, Inmaculada Tasset, Yves Robert Juste, Eva Maria Mandelkow, Eckhard Mandelkow, Ana Maria Cuervo

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish (US)
JournalAging Cell
DOIs
StateAccepted/In press - 2017

Fingerprint

Autophagy
Mutation
Tauopathies
Microtubule Proteins
tau Proteins
Poisons
Brain
Post Translational Protein Processing
Neurodegenerative Diseases

Keywords

  • Aging
  • Alzheimer's disease
  • Autophagy
  • Frontotemporal dementia
  • Lysosomes
  • Neurodegeneration

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

Interplay of pathogenic forms of human tau with different autophagic pathways. / Caballero, Benjamin; Wang, Yipeng; Diaz, Antonio; Tasset, Inmaculada; Juste, Yves Robert; Mandelkow, Eva Maria; Mandelkow, Eckhard; Cuervo, Ana Maria.

In: Aging Cell, 2017.

Research output: Contribution to journalArticle

Caballero, Benjamin ; Wang, Yipeng ; Diaz, Antonio ; Tasset, Inmaculada ; Juste, Yves Robert ; Mandelkow, Eva Maria ; Mandelkow, Eckhard ; Cuervo, Ana Maria. / Interplay of pathogenic forms of human tau with different autophagic pathways. In: Aging Cell. 2017.
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