# Reproductive Hormones - Biological and Molecular Actions

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2022 · $400,000

## Abstract

Project Summary/Abstract
REGg Regulation of Tau Protein
The proposed study will focus on regulation of Tau protein by the REGg proteasome and its causal relation to
dementia. Tau is a set of isoforms that are microtubule-associated proteins that become hyperhosphorylated
and form ’tangles’ in dementia. The common theme for Alzheimer’s Disease (AD), Parkinson’s disease (PD),
Huntington’s disease (HD) and primary ‘tauopathies’ is abnormal deposition of protein, either intracellularly or
extracellulary. Tau deposits are seen in AD and primary tauopathies, and Tau deposits appear to be the most
accurate predictor of cognitive decline in AD. Thus, a loss of regulation of protein turnover by proteasome action
and maintenance of protein homeostasis—proteostasis—appears to be common to dementias. Our group has
pioneered work on the 20S proteasome, REGg. This proteasome is ATP- and Ubiquitin-independent and
processes regulatory cellular components, including transcriptional coregulators. Our findings indicate REGg is
a key player in homeostasis of Tau. We have developed a REGg knockout (KO) mouse and a REGg
overexpressing (OE) mouse. Using these, with commercially available Tau-overexpressing mice, we have found
that: (1) the REGg proteasome digests Tau and phosphorylated Tau, implicating it in Tau proteostasis, (2) the
REGg KO mouse has decreased numbers of neurons in the hippocampus and decreased dendrite formation
compared to normal mice and (3) REGg KO mice have slower learning at 8 months than normal mice. These
findings indicate that REGg is central in maintenance of brain neurons. Recently we have defined a negative
regulator of REGg, NIP30, and found a conserved motif that is phosphorylated (‘off’ for REGg) or not (‘on’). We
have constructed phosphor-mimetic or phosphor-negative knock-in ‘on’ or ‘off’ model mice. With these
observations and tools in hand, the proposed work will test the hypothesis that REGg is required in proteostasis
of Tau and loss of its activity leads to Tau accumulation in neurons. Our efforts will include: a) characterization
of phosphorylated Tau as a target of REGg in vivo and in vitro, b) determining the mechanisms of Tau
degradation by REGg, and c) determining behavioral and learning traits that are modulated by REGg activity.
The proposed work is novel and highly feasible. Successful outcome of the studies will give us ability to measure
onset of neuronal decay at earlier stages than we presently can, and define neurodegenerative mechanisms
related to proteostasis.

## Key facts

- **NIH application ID:** 10493695
- **Project number:** 3R01HD008188-50S1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** BERT W O'MALLEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $400,000
- **Award type:** 3
- **Project period:** 1974-09-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10493695

## Citation

> US National Institutes of Health, RePORTER application 10493695, Reproductive Hormones - Biological and Molecular Actions (3R01HD008188-50S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10493695. Licensed CC0.

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