TitleInterplay of pathogenic forms of human tau with different autophagic pathways.
Publication TypeJournal Article
Year of Publication2018
AuthorsCaballero B, Wang Y, Diaz A, Tasset I, Juste YRobert, Stiller B, Mandelkow E-M, Mandelkow E, Cuervo AMaria
JournalAging Cell
Volume17
Issue1
Date Published2018 Feb
ISSN1474-9726
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.

DOI10.1111/acel.12692
Alternate JournalAging Cell
PubMed ID29024336
PubMed Central IDPMC5770880
Grant ListU54 NS100717 / NS / NINDS NIH HHS / United States
P30 DK041296 / DK / NIDDK NIH HHS / United States
RF1 AG054108 / AG / NIA NIH HHS / United States
P30 AG038072 / AG / NIA NIH HHS / United States
P01 AG031782 / AG / NIA NIH HHS / United States