# Transcriptional regulation of metabolism in neurons

> **NIH NIH R01** · SOUTHERN RESEARCH INSTITUTE · 2020 · $435,080

## Abstract

Epidemiological, genetic, and biological evidence implicates mitochondrial dysfunction in the pathogenesis of
Parkinson Disease (PD). Recent transcriptional studies have identified clusters of genes reduced in
dopaminergic neurons of the substantia nigra of patients with subclinical and symptomatic PD, the majority of
which are involved in neuronal metabolism and mitochondrial function. These findings raise the possibility that
the function of transcriptional regulators of metabolic and mitochondrial genes may be compromised in
idiopathic PD and that targeting key transcriptional pathways for gene regulation may be an appropriate
strategy for preventing and/or rescuing metabolic deficits and neuronal cell death.
 Using bioinformatics and transcriptional assays, we have identified a potential transcription factor required for
the regulation of metabolic and nuclear-encoded gene transcription in dopaminergic nigral neurons. This
protein, estrogen-related receptor γ (ERRγ), drives the expression of nuclear-encoded genes for mitochondrial
biogenesis and respiration in peripheral tissues, and it can directly associate with peroxisome proliferator-
activated receptor γ coactivator 1α (PGC-1α), a transcriptional coactivator that is reduced in PD and can be
neuroprotective when overexpressed in PD models. Our preliminary data indicate that ERRγ is expressed by
neurons of the substantia nigra in rodents and that deletion of ERRγ from the mouse midbrain causes a
reduction in ERRγ-driven metabolic genes and motor activity. Furthermore, our data indicate that PGC-1α-
target genes are enriched in binding sites for ERRγ and that PGC-1α and ERRγ can synergistically drive
mitochondrial gene expression. Importantly, the majority of mitochondrial genes of the electron transport chain
reduced in PD are ERRγ target genes. The experiments proposed in this application will expand upon these
initial findings to test the hypotheses that ERRγ is a central regulator of metabolic and mitochondrial gene
expression in nigral neurons (Aim 1), that ERRγ is required for PGC-1α to induce metabolic and mitochondrial
genes (Aim 2), and that overexpression of ERRγ can prevent cell dysfunction and death in rodent model of PD
(Aim 3). These experiments have the potential to reveal the critical pathways by which nigral neurons maintain
metabolic and mitochondrial homeostasis and a novel avenue for improving mitochondrial function in disease.
Furthermore, considering that ERRγ can orchestrate a transcriptional program for a number of genes reduced
in PD, ERRγ deletion in nigral neurons could serve as a biologically relevant model of idiopathic PD.

## Key facts

- **NIH application ID:** 9898487
- **Project number:** 5R01NS101958-05
- **Recipient organization:** SOUTHERN RESEARCH INSTITUTE
- **Principal Investigator:** Rita Marie Cowell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $435,080
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898487

## Citation

> US National Institutes of Health, RePORTER application 9898487, Transcriptional regulation of metabolism in neurons (5R01NS101958-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898487. Licensed CC0.

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