Abstract
Background
Declining 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.
Methods
Mass 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.
Results
The 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.
Conclusions
We 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.
Keywords
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Article info
Publication history
Published online: November 10, 2021
Accepted:
October 27,
2021
Received in revised form:
October 12,
2021
Received:
April 16,
2021
Footnotes
MT is currently affiliated with the School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China. CJ is currently affiliated with the Department of Neuroscience and Physiology, Neuroscience Institute, New York University School of Medicine, New York, New York.
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