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Functional and biochemical analysis of RNA exosome variants linked to neurological disorders

Award Number: F31NS147773
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: 02/01/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Functional and biochemical analysis of RNA exosome variants linked to neurological disorders - Project Summary Over 300 million individuals worldwide are affected by developmental disorders. Many such disorders arise from dysfunction of RNA-binding proteins and regulatory factors that play general roles in gene expression but often cause pathology within specific organ systems. An example of a critical RNA processing factor linked to disease is the RNA exosome, an essential and conserved 3’ to 5’ ribonuclease complex, which processes and/or degrades most types of cellular RNAs. Notably, dysfunction of the RNA exosome is associated with human diseases, termed “RNA exosomopathies”, which manifest during development and can result in neurological disorders such as microcephaly, pontocerebellar hypoplasia and motor neuron deficiencies as well as cardiac conduction and rhythm abnormalities which can cause sudden cardiac death. Patients with RNA exosomopathies rarely live beyond childhood, and the diseases currently have no treatments. RNA exosomopathies are typically caused by single amino acid changes in conserved regions of the structural subunits of the RNA exosome complex. The list of RNA exosomopathies continues to expand, highlighting the need to characterize these diseases and uncover disease mechanisms. My proposal will be the first to analyze a series of missense mutations that occur in the EXOSC5 subunit of the RNA exosome to understand how each of these changes similarly or distinctly alters RNA exosome function and leads to disease. I hypothesize that different mutations within EXOSC5 cause distinct functional changes in RNA exosome activity. Because individuals with pathogenic mutations in the EXOSC5 gene show both neurological and cardiac symptoms, I will focus on defining how a series of missense mutations in this gene impact RNA exosome activity and function using a rapid and facile system by modeling these changes in budding yeast. Thus, my studies will test this hypothesis by exploiting the Saccharomyces cerevisiae ortholog of EXOSC5, Rrp46. Due to the evolutionary, functional and structural conservation of the RNA exosome, budding yeast provides a versatile system to characterize functional consequences of changes linked to RNA exosome disease. For these aims, we have generated five rrp46 missense mutations that cause RNA exosomopathies associated with both neurodevelopmental and cardiac pathologies: rrp46-Q86I, rrp46-L127T, and rrp46-L191H (linked to different severities of cerebellar hypoplasia and risk of sudden cardiac death), a new mutant obtained from our clinical collaborators, rrp46-C202L (linked to congenital ataxia), and rrp46-V73K (linked to cardiac abnormalities). Using these models, I will: Aim 1) examine the impact of each mutation on RNA exosome function through a combination of functional assays and unbiased comparative transcriptomics; and Aim 2) examine the impact of each mutation on RNA exosome structural integrity and interactions through subunit co-migration assays and extragenic suppressor screens. Through these aims, my studies will uncover how different RNA exosome mutations impact the complex to cause distinct molecular outcomes and provide me with critical training.


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 = $50,114 )
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	1/26/2026	NEW	$0
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	4/15/2026	NEW	$576
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/26/2026	NEW	$49,538
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Functional and biochemical analysis of RNA exosome variants linked to neurological disorders

Award Number: F31NS147773

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: 02/01/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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