A Comprehensive Genetic, Transcriptomic, and Immunohistochemical Analysis of PSP - ABSTRACT The proposed project addresses critical gaps in understanding the pathogenesis of progressive supranuclear palsy (PSP), a rare tauopathy characterized by debilitating motor and cognitive impairments. PSP is distinguished by its unique neuropathological features, particularly the widespread involvement of glial cells— astrocytes and oligodendrocytes—alongside neuronal tau pathology. Despite recent advancements, the specific role of glial tau biology in PSP remains poorly understood, and this research aims to uncover the molecular mechanisms driving glial tauopathy in PSP. The study integrates cutting-edge techniques, including genome- wide association studies (GWAS), spatial transcriptomics, and multiplex immunohistochemistry, to explore the genetic, transcriptomic, and cellular factors underlying PSP. Aim 1 will identify novel genetic risk loci by expanding the cohort to include diverse populations, addressing the underrepresentation of non-European ancestries in PSP genetic studies. This expanded cohort will enable the discovery of genetic drivers that have been overlooked in previous studies, facilitating a deeper understanding of the disease's genetic architecture. Aim 2 will utilize spatial transcriptomics to generate high-resolution gene expression maps of tau-positive and tau-negative glial populations in key brain regions such as the primary motor cortex and putamen. These spatial maps will be integrated with hyperphosphorylated tau immunohistochemistry to identify molecular changes linked to tau pathology in both glial and neuronal populations. By exploring these relationships, this aim will uncover the role of glial dysfunction in PSP. Aim 3 will focus on region-specific protein markers of degeneration using immunohistochemistry, examining the expression of key neurodegenerative markers and genetic candidates. This will be done through both case-control and case-only studies to correlate proteinopathies with clinical phenotypes, tau-related pathologies, and genetic findings, providing insights into PSP heterogeneity. Furthermore, this aim will deploy A.I. based algorithms of pathology quantification on whole slide images, an approach that could be leveraged in studies of other primary and secondary tauopathies. The combination of these advanced methodologies will offer new insights into the molecular pathways that drive disease progression, particularly the role of glial cells in tauopathy. Furthermore, the focus on diverse populations will ensure that the findings are globally relevant, advancing diagnostic and therapeutic strategies for PSP and related tauopathies.
