Summary/Abstract Parkinson’s Disease (PD) is the second most common neurodegenerative disease affecting nearly one million people in the United States, and up to 80% of PD patients eventually develop Parkinson’s Disease Dementia (PDD), many with co-Alzheimer’s Disease pathology. PD is a neurodegenerative disease impacting the dopaminergic cells in the substantia nigra pars compacta (SNpc), which play a large role in controlling both movement and cognition. The motor circuit involves the lateral SNpc projections to the striatum, while dementia phenotypes involve the medial SNpc projections to various cortical and limbic related structures. To date, there are no significant therapeutics that prevent progression of disease and dementia, highlighting a critical need for further understanding of PD pathology. Notably, epigenetics has gained prominence, with histone deacetylase inhibitors showing promise for neurodegenerative diseases, including PD. Recently, H3K4me3, trimethylated histone 3 at lysine 4, has come to light as a neuroprotector in a drug induced rat model of PD. This proposal aims to interrogate a novel epigenetic marker, dopaminylation, in PD. Our lab recently established a novel role for dopamine termed dopaminylation, whereby dopamine acts as an epigenetic marker on Histone 3 glutamine 5 (H3Q5dop), adjacent to the significant H3K4me3 modification. H3Q5dop is covalently attached via the Tissue- Transglutaminase 2 enzyme to proteins and this process is concentration dependent. Given the loss of dopamine in PD, there is indeed an observed loss of H3Q5dop in postmortem human PD SNpc tissue and a global loss of dopaminylation observed in postmortem human PD post-synaptic BA25 cortical tissue. Interestingly, the loss of H3Q5dop was found in conjunction with and independent of the neighboring H3K4me3 epigenetic modification. Preliminary findings suggest that H3Q5dop plays an important role in preserving and potentiating H3K4me3 readout, possibly pointing to H3Q5dop’s role in neuroprotection as well. Thus, I hypothesize that H3Q5dop influences chromatin architecture via enhancing H3K4me3 signal, and its decrease in PD alters cellular identity, SNpc projections to key motor and cognitive brain regions, and behavior. Firstly, this proposal will interrogate H3Q5dop in human postmortem SNpc and BA25 prefrontal cortex via the integration of data from epigenetic regulation, chromatin accessibility, and gene expression. Secondly, in mouse models, this proposal will assess the loss of H3Q5dop mediated changes to transcriptional identity, SNpc projections, motor function, and emotion-based learning. This innovative work will offer novel insights into H3Q5dop’s role in the pathophysiology of PD, establishing a novel therapeutic target. This proposed research will take place at the Icahn School of Medicine at Mount Sinai, within the Friedman Brain Institute, one of the world’s premier institutions for translational brain and nervous system sciences. With...