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Nrf2 mediates the expression of BAG3 and autophagy cargo adaptor proteins and tau clearance in an age-dependent manner.

ABSTRACT: During aging, decreased efficiency of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation and autophagic processes in the brain may be a contributing factor in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease. Therefore, we analyzed the expression of Bcl-2-associated athanogene 3, a cochaperone that mediates autophagy, and the autophagy adaptors NBR1, NDP52, and sequestosome 1/p62 in the brains of 4-, 8-, and 12-month-old wild-type and Nrf2 knockout (-/-) mice. We also analyzed the levels of total tau and phospho-tau species. There were minimal differences in the expression of autophagy-related genes or tau species in 4-month-old animals; however, by 12 months, all of these autophagy-associated genes were expressed at significantly lower levels in the Nrf2 (-/-) mice. The decreases in the autophagy-associated genes were accompanied by significantly elevated levels of phospho-tau species in the 12-month-old Nrf2 (-/-) brains. These findings indicate that Nrf2 regulation of autophagy-related genes likely plays a greater role in mediating the clearance of tau as an organism ages.

SUBMITTER: Tang M

PROVIDER: S-EPMC5801049 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Nrf2 mediates the expression of BAG3 and autophagy cargo adaptor proteins and tau clearance in an age-dependent manner.

Tang Maoping M Ji Changyi C Pallo Susanne S Rahman Irfan I Johnson Gail V W GVW

Neurobiology of aging 20171209

During aging, decreased efficiency of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation and autophagic processes in the brain may be a contributing factor in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease. Therefore, we analyzed the expression of Bcl-2-associated athanogene 3, a cochaperone that mediates autophagy, and the autophagy adaptors NBR1, NDP52, and sequestosome 1/p62 in the brains of 4-, 8-, and 12-month-old wild-type and Nrf2 knockout (-/-) mice ...[more]

PMID: 29304346

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Project description:BackgroundDeclining proteostasis with aging contributes to increased susceptibility to neurodegenerative diseases, including Alzheimer's disease (AD). Emerging studies implicate impairment of the endosome-lysosome pathway as a significant factor in the pathogenesis of these diseases. Previously, we demonstrated that BAG3 regulates phosphorylated tau clearance. However, we did not fully define how BAG3 regulates endogenous tau proteostasis, especially in the early stages of disease progression.MethodsMass spectrometric analyses were performed to identify neuronal BAG3 interactors. Multiple biochemical assays were used to investigate the BAG3-HSP70-TBC1D10B (EPI64B)-RAB35-HRS regulatory networks. Live-cell imaging was used to study the dynamics of the endosomal pathway. Immunohistochemistry and immunoblotting were performed in human AD brains and in P301S tau transgenic mice with BAG3 overexpressed.ResultsThe primary group of neuronal BAG3 interactors identified are involved in the endocytic pathway. Among them were key regulators of small GTPases, such as the RAB35 GTPase-activating protein TBC1D10B. We demonstrated that a BAG3-HSP70-TBC1D10B complex attenuates the ability of TBC1D10B to inactivate RAB35. Thus, BAG3 interacts with TBC1D10B to support the activation of RAB35 and recruitment of HRS, initiating endosomal sorting complex required for transport-mediated endosomal tau clearance. Furthermore, TBC1D10B shows significantly less colocalization with BAG3 in AD brains than in age-matched controls. Overexpression of BAG3 in P301S tau transgenic mice increased the colocalization of phosphorylated tau with the endosomal sorting complex required for transport III protein CHMP2B and reduced the levels of the mutant human tau.ConclusionsWe identified a novel BAG3-TBC1D10B-RAB35 regulatory axis that modulates endosomal sorting complex required for transport-dependent protein degradation machinery and tau clearance. Dysregulation of BAG3 could contribute to the pathogenesis of AD.

Dataset Information

Nrf2 mediates the expression of BAG3 and autophagy cargo adaptor proteins and tau clearance in an age-dependent manner.

Publications

Nrf2 mediates the expression of BAG3 and autophagy cargo adaptor proteins and tau clearance in an age-dependent manner.

Similar Datasets

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