# Mechanisms of compensation for loss of brain dopamine

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2021 · $323,035

## Abstract

Project Summary/Abstract
 There is great interest in the compensatory mechanisms that may function to delay
onset of symptoms in the early/presymptomatic phase of Parkinson’s Disease. Here we use
Drosophila and mouse models of dopamine (DA) deficiency to characterize compensatory
mechanisms that may be relevant to the human condition. In the previous grant period, we
partly localized a genetic element responsible for the ‘Dopamine Bypass’ phenotype, hereafter
referred to as ‘DD-Hi’, where ‘DD’ refers to Dopamine Deficient. DD-Hi flies show near normal
levels of locomotor activity despite total deficiency of brain dopamine (DA), compared to the low
locomotor activity DA deficient line, DD-Lo. The work proposed for the upcoming grant period
will work toward more precise genetic mapping of this trait. Related aims will contribute to this
effort, identifying and characterizing a co-transmitter that functions in DA neurons that are
devoid of dopamine, and analyzing the transcriptomes of single DA neurons. We will pursue a
parallel model in mice, where mice that are made dopamine deficient in specific brain regions
provide evidence for a dopamine dependent autoregulatory loop that leads to continued
expression of a set of genes required for development and maintenance of DA neurons,
particularly in the SNc (substantia nigra pars compacta). Given the high susceptibility of SNc DA
neurons in early Parkinsons Disease, confirmation of this regulatory circuit could have both
clinical and basic science implications. Our hope is that pursuing analogous models in flies and
mice will aid in identification of conserved genes and mechanisms that will inform therapeutic
targets and strategies in humans.

## Key facts

- **NIH application ID:** 10263331
- **Project number:** 5R01GM084128-10
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** JAY HIRSH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $323,035
- **Award type:** 5
- **Project period:** 2009-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10263331

## Citation

> US National Institutes of Health, RePORTER application 10263331, Mechanisms of compensation for loss of brain dopamine (5R01GM084128-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10263331. Licensed CC0.

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