# The degradation of tau by selective autophagy

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2020 · $396,816

## Abstract

This is a fundamental basic research proposal that is focused on understanding the role of Bcl-
2-associated anthogene 3 (BAG3) in mediating selective autophagy and the turnover of tau in
neurons and how these processes change during aging. Selective autophagy is part of a cell's
protein quality control (PQC) system, which is the collection of cellular pathways that sense
damaged proteins and facilitate their removal. PQC is essential for the maintenance of the
appropriate, functional complement of proteins in a cell. Tau is a neuronally enriched
multifunctional protein. Given the importance of tau in neuronal function, understanding the
PQC processes which regulate phospho-tau species, as well as total tau levels, is of critical
importance. There is a growing awareness that selective autophagy, i.e., the specific recognition
and targeting of client proteins to the developing autophagosome is essential for effective PQC.
Chaperones and co-chaperones, along with the autophagic machinery, are key PQC players in
the process of recognizing and removing damaged proteins. The co-chaperone BAG3 is an
important player in selective autophagy and thus a pivotal player in the PQC system. Recently
we made the exciting discovery that in neurons BAG3 plays a significant role in
facilitating autophagy and directing endogenous, soluble tau to autophagy. This is of
fundamental importance because in healthy neurons autophagy is constitutively active and
plays a significant role in maintaining a functional proteome. BAG3 is a stress-induced protein
that increases during normal aging. It has been suggested that during aging the change in
cellular demands increases the use of autophagy to maintain protein homeostasis, and that
BAG3 plays an essential role in this process. Indeed, it has been documented that during aging
BAG3 levels increase in the rodent brain concurrent with an increased dependence on
autophagy for proteostasis. Therefore, understanding the role of BAG3 in autophagy and how it
functions to facilitate the clearance of soluble tau species is of fundamental significance. The
overall hypothesis of this proposal is that BAG3 is a key mediator of selective autophagy in
neurons and plays a significant role in mediating the clearance of tau. The specific aims of this
proposal are: (1) To test the hypothesis that BAG3 modulates autophagy and tau turnover
in situ and in vivo, and that during aging the dependence on BAG3 to facilitate
autophagy and tau clearance increases, (2) To identify essential features of the BAG3-
chaperone complex that mediate tau clearance, and (3) To characterize the mechanisms
that regulate BAG3 expression and tests their role in autophagy-based clearance of tau
in neurons. Currently little is known about the role of BAG3 in mediating autophagy in neurons,
as well as how it facilitates the turnover of tau; this application addresses these gaps in our
knowledge.

## Key facts

- **NIH application ID:** 9918995
- **Project number:** 5R01NS098769-04
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Gail V. W. Johnson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $396,816
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918995

## Citation

> US National Institutes of Health, RePORTER application 9918995, The degradation of tau by selective autophagy (5R01NS098769-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9918995. Licensed CC0.

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