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RNA editing dysregulation in the pathogenesis of Dementia and Parkinson’s disease

Award Number: R01NS148223
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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RNA editing dysregulation in the pathogenesis of Dementia and Parkinson’s disease - Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are characterized by the accumulation of proteinaceous inclusions within the nervous system. Genetics has indicated that protein homeostasis, mitochondria, and protein trafficking are major pathways that contribute to disease. We recently discovered that proteostasis failure in DLB and PD results in the accumulation of nuclear inclusions comprised of RNA binding proteins (RBPs) NONO and SFPQ. Pathologically, these inclusions increase adenosine-to-inosine (A-to-I) RNA editing by reducing the transcription of ADAR3, the inhibitor of A-to-I RNA editing. NONO and SFPQ also preferentially sequester A-to-I edited mRNAs. Our previous work showed that A-to-I editing can increase the binding to NONO/SFPQ inclusions, and further template their aggregation. Bulk RNA sequencing showed that increased editing occurs in over 3000 sites in 1600 transcripts in synucleinopathy patient iPSC-derived neurons. Among the top networks were transcripts encoding mitochondrial, ER-Golgi trafficking, or axon/synaptic maintenance proteins, which overlaps with PD/DLB genetic pathways and pathophysiology. However, the composition of mRNAs sequestered by NONO/SFPQ inclusions and the initial events that trigger inclusion formation is unknown. Furthermore, the downstream effect that A-to-I editing has on protein expression and function is unknown. Here we will address these critical questions in 3 aims using both iPSC-derived cortical neurons to model dementia-related phenotypes, and midbrain neurons to model both early and late stages of DLB, PD, and PD-Dementia. Studies will be validated in post-mortem Dementia with Lewy body patient brain. Aim 1 will determine how A-to-I editing influences subcellular location of RNA and define the specific mRNAs sequestered within NONO/SFPQ inclusions. Aim 2 will assess the connection between mitochondrial and ER- Golgi stress and NONO/SFPQ/RNA inclusion formation. Aim 3 will delineate the downstream effects that A-to-I editing has on protein expression and function by Ribosome foot-printing and prioritizing select model transcripts involved in mitochondrial, ER-Golgi trafficking, or axon/synaptic maintenance. Our studies will contribute to delineating the mechanism of A-to-I editing in synucleinopathies, and link the editing changes we previously observed to established genetic pathways associated with DLB and PD. Our mechanistic studies may uncover new methods to clear NONO/SFPQ aggregates and restore neuronal health in dementia patients. Since A-to-I editing and paraspeckles are both involved in controlling the expression of synapse/axon maintenance proteins, are studies may apply to many types of neurological disorders characterized by early synapse loss.


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 = $634,938 )
2026	2026	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/11/2026	NEW	$634,938
														Subtotal = $634,938

Grand Total All Awards = $634,938

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RNA editing dysregulation in the pathogenesis of Dementia and Parkinson’s disease

Award Number: R01NS148223

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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