# BAG3 as a proteostatic hub regulating neuronal health

> **NIH NIH R56** · UNIVERSITY OF ROCHESTER · 2020 · $307,721

## Abstract

Age is the primary risk factor for numerous neurodegenerative diseases, with Alzheimer’s disease (AD) being
the most prevalent. During aging there is a decline in protein quality control systems in general and the
vacuolar dependent degradative pathways more specifically. Indeed, dysfunction of both autophagy and
endolysosome systems occurs early in the pathogenesis of AD and impairment of these pathways likely
contributes to the accumulation and mislocalization of tau, which plays an indispensable role in the
pathogenesis of AD. Recent data provide compelling evidence that the stress responsive, multi-domain co-
chaperone, Bcl-2-associated anthogene 3 (BAG3) plays a key role in maintaining proteostasis; decreased
levels result in increased levels of phospho-tau and decreases in autophagosome-lysosome fusion. Further,
our preliminary data indicate that BAG3 likely plays a key role in vacuolar dependent degradative processes
beyond autophagy thus may be considered as a “master regulator” of neuronal proteostasis. The
UNDERLYING PREMISE of this proposal is that in neurons BAG3 plays a critical role in mediating vacuolar
dependent degradative pathways, and thus the turnover of tau. The importance of BAG3 in mediating
neuronal proteostasis is illustrated by the fact that BAG3 not only plays a key role in protecting neurons from
the accumulation of pathological tau species, but also facilitates the autophagic clearance of other disease
relevant proteins such as α-synuclein. Nonetheless, our understanding of how BAG3 regulates autophagy and
the endolysosome pathways is very limited. CRITICAL KNOWLEDGE GAPS include: understanding the
specific impact of BAG3 on vacuolar-mediated proteostatic processes as a function of age, the role of BAG3 in
mediating endocytosis, as well as how it regulates extracellular tau uptake and processing, and the role BAG3
in exosome formation and release, as well as the targeting of tau to this vesicular pool. Considering these
critical knowledge gaps the OVERALL HYPOTHESIS of this proposal is that that BAG3 is a “proteostatic hub”
that regulates vacuolar -based pathways to maintain a functional neuronal proteome. In the context of this
overall hypothesis the specific aims of this proposal are: (1) To elucidate the role of BAG3 in mediating basal
and stress-induced autophagy both in vitro and vivo, (2) To test the hypothesis that BAG3 regulates the
endolysosome pathway and this impacts the processing of endogenous tau (including exosome formation and
release, and targeting of tau to this pool) and (3) To test the hypothesis that BAG3 mediates endocytosis and
thus uptake and trafficking of exogenous tau. These studies will be carried out using both primary neuron
cultures and mouse models. All in vivo studies will be carried out in male and female mature, middle-aged and
old mice to determine how age influences the effects of BAG3 on these vacuolar dependent degradative
systems. The IMPACT of these studies will be to provide c...

## Key facts

- **NIH application ID:** 10232974
- **Project number:** 1R56AG067739-01
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Gail V. W. Johnson
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $307,721
- **Award type:** 1
- **Project period:** 2020-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10232974

## Citation

> US National Institutes of Health, RePORTER application 10232974, BAG3 as a proteostatic hub regulating neuronal health (1R56AG067739-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10232974. Licensed CC0.

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