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Neuroinflammatory Epitranscriptomic Mechanisms in Parkinson's Disease

Award Number: RF1NS141022
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: 05/08/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Neuroinflammatory Epitranscriptomic Mechanisms in Parkinson's Disease - Abstract The accumulation of alpha-synuclein (αSyn) aggregates is a hallmark of various synucleinopathies including Parkinson’s disease (PD) and dementia with Lewy bodies. Neuroinflammation plays a pivotal pathophysiological role in the progression of dopaminergic neurodegenerative processes in PD. Aggregated αSyn has emerged as a predominant pathological trigger for microglial activation and the subsequent release of proinflammatory cytokines and chemokines in the brain. Moreover, the transmission of αSyn aggregates from affected neurons to other brain cells, including microglia, contributes to heightened neuroinflammatory responses. We recently reported that the Fyn-PKCδ kinase signaling axis undergoes rapid activation in microglia upon αSyn fibril (αSynf) stimulation and plays a significant proinflammatory role by activating multiple cyto/chemokine levels including TNF-α, IL-6, and IL-12. Despite these advancements, the exact upstream neurobiological mechanisms regulating the dynamics of various cyto/chemokine synthesis in microglial cells in response to αSynf remain undefined. In the emerging field of epitranscriptomics, N6-methyladenosine (m6A) mRNA modification has been shown to regulate the fate of various transcripts including immune inflammatory factors. In our proteomic analysis, we unexpectedly observed rapid induction of the m6A demethylase ALKBH5 in αSynf-stimulated microglial cells. Since ALKBH5 is a major regulator controlling the rate of cytokine and chemokine transcripts in immune cells, this proposal aims to determine its role in neuroinflammatory processes underlying PD. Interestingly, we found that ALKBH5 is also upregulated in animal models of PD, and more importantly, in postmortem human PD brains. Our preliminary mechanistic studies further identified that phosphorylation of ALKBH5 by PKCδ modulates its subcellular localization and demethylase activity in response to αSynf. Loss-of-function studies revealed a pro-inflammatory role for elevated ALKBH5 in αSynf- stimulated microglia, leading to the novel hypothesis that αSynf induces a proinflammatory response in microglia by upregulating and translocating ALKBH5 in a Fyn-PKCδ-dependent manner. Thus, the following specific aims will be pursued to further expand our novel findings: (1) Characterize the ALKBH5 upregulation and subcellular translocation and their roles in regulating microglial activation using cell and animal models of αSyn-induced neuroinflammation; (2) Determine whether Fyn-PKCδ signaling regulates the proinflammatory function of ALKBH5 in cell and animal models of αSyn-induced neuroinflammation; and (3) Establish the proinflammatory function of ALKBH5 in progressive animal models of α-synucleinopathy and evaluate the translational utility of the Fyn-PKCδ-ALKBH5 signaling axis in neuroinflammatory models of PD. Taken together, our proposal will offer novel mechanistic insights into the progression of neurodegenerative processes in PD and related synucleinopathies. Additionally, it has the potential to translate these mechanistic findings into effective therapies for neurodegenerative diseases.


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 = $1,297,188 )
2026	2026	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/12/2026	NEW	$1,297,188
														Subtotal = $1,297,188

Grand Total All Awards = $1,297,188

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Neuroinflammatory Epitranscriptomic Mechanisms in Parkinson's Disease

Award Number: RF1NS141022

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: 05/08/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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