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. Project Number: 1R01NS148223-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Joseph Mazzulli | Institution: NORTHWESTERN UNIVERSITY, CHICAGO, IL | Award Amount: $634,938 | Activity Code: R01 | Study Section: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND] View on NIH RePORTER: https://reporter.nih.gov/project-details/11340839