Mapping the Epigenomic and Spatial Transcriptomic Landscape in Parkinson's Disease - Project Summary Alzheimer’s disease (AD) and Alzheimer’s disease-related dementia (ADRD) and Parkinson’s disease (PD) are chronic neurodegenerative disorders characterized clinically by cognitive impairment and neuropathologically by abnormal protein accumulations (Aβ and α-Synuclein). Recent advances in understanding transcriptomic changes in AD and PD have focused on specific cell subpopulations and brain regions, such as microglia in the parahippocampal gyrus in AD and dopaminergic neurons in the substantia nigra in PD. Although significant, this narrow focus has diverted attention on other cell types and brain regions implicated in those diseases. Recognizing this shortfall, our project broadens the scope of studied cell subpopulations and brain regions with a special emphasis on deciphering impaired cellular cross-talk, detecting perturbed spatial interactions with morphological markers, and identifying gene regulatory programs driving AD and PD progression. In our previous work, we have established two resources through single-nuclei profiling. The first is a cross-disorder atlas that includes data from the prefrontal cortex of 1,494 donors with seven major brain-related disorders, including AD, PD, and other dementia. The second is a PD-specific atlas derived from 100 PD donors, encompassing five different brain regions. Our current proposal aims to leverage data from both AD/ADRD and PD datasets to systematically describe the differences in the transcriptional landscape of those diseases and augment the PD-centric atlas by integrating epigenomics and spatial transcriptomics. In Aim 1, we will characterize shared and distinct transcriptional changes between AD, PD and related dementia and identify cell types with significant proportional shifts associated with the disease progression. For the prefrontal cortex, included in both previously generated resources, we will conduct detailed comparative analyses between those diseases with a special focus on the interplay between AD and PD neuropathology measured by the Braak scoring system, i.e. accumulation of neurofibrillary tangles and Lewy bodies. Aim 2 focuses on developing an atlas of brain regulome changes in PD, which will pinpoint altered epigenetic regions leading to disruptions in chromatin structure. Utilizing both epigenomics and transcriptomics data will help us uncover enhancer-driven gene regulatory networks and model how these networks shape the transcriptome during disease progression by manipulating key epigenome regulators and related TFs. By integrating epigenome data with genome-wide association studies on PD, we will identify cell subtypes with increased PD heritability and refine the mapping between risk loci and the causal genes. Aim 3 will utilize integrative spatial genomic assays to detect differential cell-to-cell interaction networks, pointing to the gain or loss of ligand-receptor relationships and spatial relationships with morphological markers. Collectively, these studies will enable us, at unprecedented resolution, to explore brain region- and cell-type-specific transcriptomics and epigenomics responses in PD and distinguish them from those employed in AD and ADRD.
