The underlying causes of neuronal cell loss in Parkinson's disease (PD) and related synucleinopathies, including Lewy Body Dementia (LBD) and Multiple System Atrophy (MSA), remain elusive. There is compelling evidence suggesting that alterations in histone acetylation play a significant role in cognition and brain function, and that aberrant histone acetylation is associated with both, neurodegenerative diseases and aging. However, our understanding of the underlying molecular and cellular mechanisms driving changes in histone acetylation, and how dysregulated histone acetylation contributes to age-related neurodegenerative disorders such as PD, Alzheimer's disease (AD), and related dementias (ADRD) remains limited. To comprehensively explore the role of histone acetylation in the development of PD, LBD and MSA, we established a novel human pluripotent stem cell (hPSC)-based discovery platform. This platform offers a robust and screenable experimental system that replicates many disease-relevant characteristics within neuronal cells. Using this discovery platform, we employed a combination of SILAC proteomics and genome-wide CRISPR screening to identify modifiers of histone acetylation that contribute to α-Synuclein (α-Syn) pathology. Consistent with these in vitro results, we find similar changes in postmortem brain tissue sample from PD patients. Given that one of the primary functions of histone acetylation is to regulate gene expression, we speculate the dysregulated transcription, resulting from α-Syn-mediated disruption of histone acetylation modifying enzymes, contributes to the neurodegeneration seen in PD, LBD and related synucleinopathies. The main goal of this proposal is to elucidate the functional significance of histone acetylation in pathogenesis of PD, LBD and related synucleinopathies. Our approach involves a wide range of disease-relevant hPSC-based cellular model systems to investigate the impact of modulating histone acetylation, through disrupting or enhancing the activity of histone acetylation modifying enzymes, on α-Syn-mediated neuronal dysfunction and neurodegeneration. Furthermore, we will employ molecular and epigenomics techniques to define the epigenetic alterations and chromatin-regulated gene expression signatures linked to α-Syn pathology. Given that α-Syn pathology is the defining characteristic of PD, LBD and MSA and is frequently observed as co-pathological feature in AD and ADRD, we will extend our molecular and epigenetic investigations to include a broad range of postmortem brain tissue samples from patients. Thus, we aim to establish a correlation between α-Syn pathology and aberrant histone acetylation as a common feature in PD and ADRD. The proposed experiments hold the potential to provide novel mechanistic insights into the epigenetic aspects of PD, LBD and related synucleinopathies. As drugs targeting histone modifiers are currently under development as potential therapeutics for various conditions, th...