# Elucidating a Role for A Transcription Factor in Neuronal Proteostasis

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $37,835

## Abstract

Project Summary
Sporadic neurodegenerative disorders are prevalent in the aging population, yet their origins remain difficult to
explain and treatment regimens often of limited effectiveness. Though tremendous diversity exists in the
specific cell types or regions of the CNS affected between these diseases, they are linked by a common
characteristic: the formation of protein aggregates in or surrounding dying cells. Insights gleaned from the
study of loss of function mutations that predictably confer the formation of protein aggregates in neurons and
subsequent neuron death, allow us to uncover proteostatic pathways essential for neuron survival that may be
disrupted in both sporadic and familial forms of human neurodegenerative disorders.
Our lab uses a forward genetic approach to identify homeostatic pathways critical to neuron function and
survival. Recently we discovered a spontaneous mutation in mice that leads to the formation of protein
aggregates followed by progressive loss of cerebellar Purkinje cells and ataxia beginning at 1 month of age in
mice that are homozygous for this mutation. By positional cloning, we identified a mutation in the Rreb1 zinc
finger transcription factor that co-segregates with aggregate formation, neuron loss, and ataxia. Interestingly,
heterozygosity for this mutation is also associated with Purkinje cell loss, although the onset of neuron death is
later and less severe, suggesting that loss of Rreb1 function and neuron survival are tightly linked at the
dosage level.
Few transcription factors have been associated with loss of neuronal proteostasis with most studies focused on
the production and/or clearance of misfolded proteins caused by dominant mutations in genes encoding these
proteins. Though little is known about the role of Rreb1 in the nervous system, several studies have focused on
the role of this protein in regulating transcription in development, citing its ability to bind directly to DNA via
several zinc finger domains and recruit histone deacetylases, histone demethylases, and co-repressor
complexes to remodel chromatin and ultimately control gene expression. Using this novel model of
neurodegeneration, I will investigate the role of Rreb1 in neurons and determine how the disruption of this
gene leads to an imbalance in proteostasis and ultimately neuron cell death.

## Key facts

- **NIH application ID:** 9992736
- **Project number:** 1F31NS117131-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Emily Griffin
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,835
- **Award type:** 1
- **Project period:** 2020-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9992736

## Citation

> US National Institutes of Health, RePORTER application 9992736, Elucidating a Role for A Transcription Factor in Neuronal Proteostasis (1F31NS117131-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9992736. Licensed CC0.

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