Dysregulation of Histone Acetylation in Parkinson's Disease

Albert Einstein College Of Medicine, Bronx NY

Investigators

Abstract

The etiology leading to neuronal cell loss in Parkinson’s disease (PD) and related synucleinopathies including Lewy Body Dementia (LBD) and Multiple system atrophy (MSA) remains unknown. There is compelling evidence that changes in histone acetylation are implicated in cognition and brain function and that aberrant histone acetylation is associated with neurodegenerative diseases and aging. However, there is currently no mechanistic insight about the cause and how dysregulated histone acetylation is functionally linked to age-related neurodegenerative disorders such as PD and Alzheimer's disease (AD) and related dementias (AD/ADRD). To functionally investigate the role of histone acetylation in the pathogenesis of PD and related synucleinopathies, we have developed a hPSC-based discovery platform that provides a robust, and screenable experimental system with disease-relevant phenotypes in neuronal cells. Using this discovery platform, we intersected SILAC proteomics and genome-wide CRISPR-screening data and identified modifiers of histone acetylation to contribute to a-Syn toxicity. Consistent with these in vitro results, we find similar changes in patients’ postmortem brain tissue. Considering that a key function of histone acetylation is to modulate gene expression, we speculate the dysregulated transcription, resulting from a-Syn-mediated disruption of histone acetylation modifying enzymes, contributes to the neurodegeneration in PD and related synucleinopathies. The main goal of this proposal is to determine the functional role of histone acetylation in PD and related synucleinopathies at the molecular and cellular level. Specifically, we will apply our novel functional genomics platform to determine the effect of modulating histone acetylation by gain and loss of function of acetylation modifying enzymes in a-Syn-mediated impairment of neuronal function and neuronal cell death. In addition, we will use molecular and epigenomics approaches to identify the chromatin regulated gene expression signature associated with a-Syn toxicity. Given that a-Syn pathology is a key feature of PD, LBD, and MSA, as well as a common co-pathology in AD/ADRD, we will expand our molecular and epigenetic analysis to include a wide range of patient-derived hiPSC-based models and postmortem brain tissue to confirm that aberrant histone acetylation plays a central role in the pathogenesis of PD and related pathologies. The proposed experiments hold the potential to offer essential mechanistic insights into the epigenetics of PD and related synucleinopathies. Given that drugs targeting histone modifiers are currently being developed as therapeutics, there is considerable interest in understanding how modulating histone acetylation could be used to treat neurodegenerative disease, cognitive decline, and aging. Importantly, the integration of our findings with available data for aging and AD will allow the interpretation of PD-associated epigenetic changes in a broader context of neurodegenerative diseases and aging and provide a molecular starting point to functionally understand how genetic and non-genetic factors interact in the etiology of complex neurodegenerative diseases.