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

Award Number: F31NS139652
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/07/2024
PERIOD OF PERFORMANCE END DATE: 12/06/2027

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $44,153 )
2026	2026	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	4/15/2026	NON-COMPETING CONTINUATION	$576
2026	2026	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/18/2025	NON-COMPETING CONTINUATION	$43,577
														Subtotal = $44,153

Issue Date FY: 2024 ( Subtotal = $42,269 )
2024	2024	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/1/2024	NEW	$42,269
														Subtotal = $42,269

Grand Total All Awards = $86,422

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

Award Number: F31NS139652

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/07/2024

PERIOD OF PERFORMANCE END DATE: 12/06/2027

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