# Function and dysfunction of REST in neurodegeneration

> **NIH NIH K22** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $13,142

## Abstract

Abstract
The repressor element 1-silencing transcription factor/neuron-restrictive silencer factor, (REST/NRSF), a
transcriptional regulator of neuronal genes during development, has a crucial neuroprotective function in the
adult brain. Downregulated in mature neurons, REST is reactivated with normal aging and with cellular stress,
regulating a gene network that promotes neuronal survival and reducing the expression of genes related to the
amyloid and tau neuropathology of Alzheimer’s disease and Down syndrome. Moreover, REST activity has
been shown to be diminished in Alzheimer’s disease and Down syndrome brains. We will evaluate whether
genetically encoding high levels of REST activity and responsiveness results in neuroprotection from stress in
induced pluripotent stem cell (iPSC)-derived neurons generated from a large group of deeply phenotyped
humans from three cohorts: aged individuals with high amyloid and tau pathology and severe dementia at
death, age-matched controls, and aged individuals who died with substantial amyloid neuropathology but no
cognitive impairment. We also will examine the ability of REST to alleviate neurodegenerative phenotypes in
Down syndrome and Alzheimer’s disease human iPSC-derived neurons. Last, we will examine if REST can
rescue neurons from the synapse-damaging environment of the aged, demented brain. Our proposed studies
will probe intrinsically encoded REST activity and its role in neuroprotection in human neurons encompassing
diverse genetic backgrounds and phenotypes. These studies also will interrogate REST’s potential as a
therapeutic target in neurodegenerative diseases and will examine the importance of REST function in synaptic
plasticity. Completion of this research plan will provide training in key technical areas in which I have no
previous research experience: collecting and analyzing -omics-level data, gene editing, and measuring and
analyzing synaptic activity. This research and training in new techniques will occur in concert with an ambitious
career development plan. This will include coursework in neuroscience and bioinformatics, mentoring, grant
writing, and scientific presentations. Mentored training in these scientific areas along with execution of my
plans for further career development will be instrumental for my advancement to the position of independent
investigator and for achieving my future scientific goals in the field of neuroscience and neurological disease.

## Key facts

- **NIH application ID:** 10164877
- **Project number:** 5K22NS107802-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Marty Fernandez
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $13,142
- **Award type:** 5
- **Project period:** 2019-05-01 → 2021-06-18

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10164877

## Citation

> US National Institutes of Health, RePORTER application 10164877, Function and dysfunction of REST in neurodegeneration (5K22NS107802-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10164877. Licensed CC0.

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