# BAG3 regulates Rab35 and the ESCRT/endolysosome pathway

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2021 · $436,305

## Abstract

Protein quality control systems are essential for maintaining neuronal health, with vacuolar dependent pathways
playing a primary role in these systems. The endolysosome system is a major contributor to the maintenance of
the neuronal proteome, and dysfunction of this system occurs early in the pathogenesis of Alzheimer’s disease
(AD) , and likely contributes to the accumulation and mislocalization of tau, which plays a key role in disease
pathogenesis. Recent data provide compelling evidence that the stress responsive, multi-domain protein, Bcl-2-
associated anthogene 3 (BAG3) plays a role in maintaining protein homeostasis and neuronal health. The
expression of BAG3 in specific neuronal populations positively correlates with resistance to the development of
tau pathology in AD. Further, our preliminary data indicate that BAG3 is an upstream regulator of vacuolar
dependent pathways. The UNDERLYING PREMISE of this proposal is that in neurons, BAG3 plays a critical
role in mediating vacuolar dependent pathways, and thus proteostasis and neuronal integrity. The importance
of BAG3 in mediating proteostasis is illustrated by the fact that BAG3 not only plays an important role in protecting
neurons from the accumulation of pathological tau species, but also likely supports synaptic structure.
Nonetheless, our understanding of the mechanisms by which BAG3 regulates vacuolar dependent processes is
very limited. Although previous studies have implicated BAG3 as a mediator of autophagy, we are the first to
present evidence that BAG3 is a regulator of the endolysosome pathway. Further, our preliminary findings
implicate BAG3 as an important modulator of endosomal sorting required for transport (ESCRT) machinery.
BAG3 interacts withTBC1D10B, the primary GTPase activating protein (GAP) for Rab35, which facilitates the
recruitment of the ESCRT machinery and protein clients to the endosome, as well as mediating other vacuolar
dependent processes. The conceptual framework that BAG3 acts upstream of vacuolar pathways through its
regulation of Rab35 activity is novel and innovative. The OVERALL HYPOTHESIS of this proposal is that the
BAG3-TBC1D10B-Rab35 signaling axis regulates endosome-lysosome function and neuronal health. In
the context of this overall hypothesis the specific aims of this proposal are: to test the hypotheses that: (1) the
BAG3-TBC1D10B-Rab35 signaling axis regulates ESCRT and the endolysosome pathway, (2) in vivo BAG3
and Rab35 coordinate to mediate neuronal ESCRT/vacuolar processes, and contribute to the maintenance
synaptic integrity, and (3) the BAG3-TBC1D10B-Rab35 axis plays a critical role in regulating the clearance of
pathological tau species. These studies will be carried out using mouse models and primary neuron cultures.
The IMPACT of these studies is that they will provide crucial new insights into the mechanisms by which BAG3
acts as an upstream mediator of the endolysosome systems to maintain a healthy neuron. Overall these studie...

## Key facts

- **NIH application ID:** 10269305
- **Project number:** 1R01AG073121-01
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Gail V. W. Johnson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $436,305
- **Award type:** 1
- **Project period:** 2021-08-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10269305

## Citation

> US National Institutes of Health, RePORTER application 10269305, BAG3 regulates Rab35 and the ESCRT/endolysosome pathway (1R01AG073121-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10269305. Licensed CC0.

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