Role of N6METHYLADENOSINE (M6A) reader protein YTHDF1 in microglial mediated neuroinflammation in parkinson's disease models

The National Institute of Neurological Disorders and Stroke awarded the University of Georgia Research Foundation $131,676 on July 27, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to support research investigating the role of the N6-methyladenosine reader protein YTHDF1 in microglial-mediated neuroinflammation in Parkinson's disease models.

The research examines how YTHDF1 dysregulation contributes to alpha-synuclein-induced microglial activation and the resulting neuroinflammatory cascade that drives dopaminergic neurodegeneration in Parkinson's disease, dementia with Lewy bodies, and mixed etiology dementia. Preliminary work demonstrates that YTHDF1 is downregulated in alpha-synuclein-treated microglia and may preferentially target proinflammatory messenger RNA transcripts including TNFα, IL-6, and IL-1β. The research will characterize the functional mechanisms by which protein kinase C delta phosphorylates YTHDF1 and will explore whether restoring YTHDF1 function represents a therapeutic pathway to suppress microglia-driven neuroinflammation.

Performance occurs at the University of Georgia Research Foundation in Athens, Georgia, with a period of performance from the award date through August 31, 2028. This is a Project Grant, a standard assistance type within the NINDS extramural research portfolio.

Abstract

Parkinson's disease (PD), dementia with lewy bodies (DLB) and other mixed etiology dementia (MED)-related diseases are associated with an abnormal accumulation of pathological α-synuclein (αsyn) in the basal ganglia, including the substantia nigra (SN). Pathological αsyn accumulates in lewy bodies (LBS) and is known to promote neuroinflammatory and neurodegenerative processes, specifically the loss of dopaminergic (daergic) neurons. Neuroinflammation, chronic glial activation and sustained secretion of proinflammatory cytokines and chemokines, results in exacerbation of nigral neurodegeneration in PD. The N6-methyladenosine (M6A) mrna modification is the most abundant mrna modification in eukaryotes. Emerging evidence has demonstrated proinflammatory microglia display a unique M6A mrna profile, thus suggesting M6A mrna dysregulation may contribute to αsyn-induced microglia-driven neuroinflammation. The M6A pathway, known to be highly dynamic and reversible, contains "writer", "eraser", and "reader" proteins. We recently demonstrated that METTL3 and YTHDF2, an M6A writer and reader, respectively, are dysregulated in models of neurotoxicity-linked PD. Other work has shown that YTHDF1, a translation-promoting M6A reader protein, plays vital roles in memory-related brain function and is uniquely dysregulated in MED-related diseases. We have recently obtained exciting data demonstrating YTHDF1 is downregulated in αsyn-induced microglial activation. Our preliminary functional studies indicate YTHDF1 may preferentially target certain proinflammatory mrna transcripts such as tnfα, IL- 6 and IL-1Β-all linked to the neuroinflammatory process in PD. Additionally, striking evidence suggests protein kinase c delta (pkcδ) phosphorylates YTHDF1 following αsyn treatment in microglia. These novel observations prompted US to hypothesize the YTHDF1 reader preferentially targets proinflammatory mrna for efficient translation in αsyn-induced neuroinflammation in microglia through post-translation modification mediated by pkcδ. To test this hypothesis, the following specific aims will be pursued: (i) identify pkcδ mediated-YTHDF1 post-translational modification sites and RNA-binding dynamics in pathological αsyn- treated microglial cells, and (II) determine the functional consequence of αsyn-mediated microglial activation on YTHDF1 spatiotemporal expression changes, phosphorylation status, interactome profile and mrna targeting in a progressive PD animal model of synucleinopathy. We will adopt innovative methodologies including MS- phospho-proteomics, RNA – immunoprecipitation sequencing (RIP-SEQ), transcriptomics, and proximity- dependent biotin identification (turboid). Overall, this F31 training proposal will provide novel molecular insights into the M6A/YTHDF1-dependent regulatory mechanisms in microglia-driven chronic neuroinflammation in PD, allowing future studies to focus on relevant therapeutic approaches. Importantly, this exciting project will allow me to hone my interdisciplinary training integrating biochemistry, molecular biology and neuroscience, ultimately enabling me to pursue my independent scientific career in the field of molecular neurodegeneration.