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TitleDysregulation of autophagy and stress granule-related proteins in stress-driven Tau pathology
Author(s)Silva, Joana Margarida Gonçalves Mota
Rodrigues, Sara
Marques, Maria Belém Sousa Sampaio
Gomes, Patrícia
Carvalho, Andreia Alexandra Neves
Dioli, Chrysoula
Cunha, Carina Isabel Soares
Mazuik, Brandon F.
Takashima, Akihiko
Ludovico, Paula
Wolozin, Benjamin
Sousa, Nuno
Sotiropoulos, I.
Issue date2019
PublisherSpringer Nature
JournalCell Death and Differentiation
CitationSilva, J. M., Rodrigues, S., Sampaio-Marques, B., Gomes, P., Neves-Carvalho, A., Dioli, C., ... & Wolozin, B. (2019). Dysregulation of autophagy and stress granule-related proteins in stress-driven Tau pathology. Cell Death & Differentiation, 1
Abstract(s)Imbalance of neuronal proteostasis associated with misfolding and aggregation of Tau protein is a common neurodegenerative feature in Alzheimer's disease (AD) and other Tauopathies. Consistent with suggestions that lifetime stress may be an important AD precipitating factor, we previously reported that environmental stress and high glucocorticoid (GC) levels induce accumulation of aggregated Tau; however, the molecular mechanisms for such process remain unclear. Herein, we monitor a novel interplay between RNA-binding proteins (RBPs) and autophagic machinery in the underlying mechanisms through which chronic stress and high GC levels impact on Tau proteostasis precipitating Tau aggregation. Using molecular, pharmacological and behavioral analysis, we demonstrate that chronic stress and high GC trigger mTOR-dependent inhibition of autophagy, leading to accumulation of Tau aggregates and cell death in P301L-Tau expressing mice and cells. In parallel, we found that environmental stress and GC disturb cellular homeostasis and trigger the insoluble accumulation of different RBPs, such as PABP, G3BP1, TIA-1, and FUS, shown to form stress granules (SGs) and Tau aggregation. Interestingly, an mTOR-driven pharmacological stimulation of autophagy attenuates the GC-driven accumulation of Tau and SG-related proteins as well as the related cell death, suggesting a critical interface between autophagy and the response of the SG-related protein in the neurodegenerative potential of chronic stress and GC. These studies provide novel insights into the RNA-protein intracellular signaling regulating the precipitating role of environmental stress and GC on Tau-driven brain pathology.
Publisher version
AccessOpen access
Appears in Collections:ICVS - Artigos em Revistas Internacionais com Referee

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