# A transcriptomics-based approach to identify quantitative biomarkers for multiple system atrophy

> **NIH NIH F31** · COLORADO STATE UNIVERSITY · 2024 · $42,269

## Abstract

PROJECT SUMMARY
 Multiple system atrophy (MSA), an invariably fatal neurodegenerative disorder with no disease-
modifying therapeutics or biomarkers, is characterized by the presence of pathogenic α-synuclein (α-syn) in
the brain. Whether the onset of clinical signs is due to gain-of-function (GOF) deficits arising from toxic protein
aggregation or from the loss-of-function (LOF) consequences due to α-syn sequestration remains a subject of
debate. My objective is to identify MSA-driven changes in neuronal gene expression that may serve as novel
biomarkers. Rather than an either-or scenario, I hypothesize that in MSA patients, a combination of the gain of
toxic function of α-syn with the loss of normal function contributes to disease pathogenesis. My approach will
draw from the expertise of both my sponsor (Dr. Woerman) and co-sponsor (Dr. Regan) to use an unbiased
approach to interrogate the GOF vs LOF debate while also identifying potential quantitative biomarkers for
MSA. Specific Aim 1 will identify and interrogate distinct changes in gene expression in response to MSA. I will
investigate the effect of MSA-induced changes on neuronal gene expression using RNA sequencing (RNA-
Seq) on human iPSC-derived dopaminergic neurons infected with MSA α-syn. I will validate hits via ELISA or
Western blot using frozen brain tissue from MSA and control patients. Additional time course studies in a
mouse model of MSA will be paired with qRT-PCR to identify genes with altered expression throughout
disease, which will determine differentially expressed genes that may be used as quantifiable biomarkers for
MSA. Specific Aim 2 will determine the effect of MSA on RNA stability. In light of recent findings demonstrating
that α-syn interacts with P-bodies, I hypothesize that α-syn accumulation in MSA affects mRNA stability,
leading to LOF deficits through altered gene expression. I will test this hypothesis by infecting human iPSC-
derived dopaminergic neurons with MSA α-syn and then performing an ActinomycinD pulse time-course assay
to measure the decay rate for mRNA. RNA-Seq will then be used to determine differentially expressed genes
due to altered mRNA stability. Together, these studies will provide critical knowledge about the consequences
of α-syn sequestration on mRNA stability and neuronal gene expression. Given the lack of biomarkers,
diagnostics, or disease-modifying therapeutics for MSA, this work will enable future studies focused on MSA
patient stratification and the development of a quantitative biomarker that can be used to determine therapeutic
efficacy in clinical trials.

## Key facts

- **NIH application ID:** 10998160
- **Project number:** 1F31NS139652-01
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Chase Reza Khedmatgozar
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $42,269
- **Award type:** 1
- **Project period:** 2024-12-07 → 2027-12-06

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998160

## Citation

> US National Institutes of Health, RePORTER application 10998160, A transcriptomics-based approach to identify quantitative biomarkers for multiple system atrophy (1F31NS139652-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10998160. Licensed CC0.

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