Gene Expression Studies in Progressive Supranuclear Palsy

Progressive supranuclear palsy (PSP) is a rapidly progressive neurodegenerative disorder with clinicopathologic heterogeneity and without any therapies. A PSP genome-wide association study (GWAS) identified six novel risk loci, in addition to the established H1 haplotype on chromosome 17 at the tau gene (MAPT) locus. The effective translation of these findings to therapy requires identification of the disease gene, the functional variants and their mechanism of action. These goals cannot be achieved by the disease GWAS alone and require alternative, powerful and mechanistic approaches.

Dr. Ertekin-Taner's laboratory leads a project that aims to close this knowledge gap by integrative analysis of multiomics measures (transcriptome, genetics and epigenomics data), with quantitative neuropathology. In collaboration with the director of Mayo Clinic's brain bank, Dennis W. Dickson, M.D., the team is using brain samples from autopsied PSP subjects with neuropathology measures for different tau pathological features of PSP: neurofibrillary tangles (NFT), tufted astrocytes (TA), tau threads (TAUTh) and coiled bodies (CB). The long-term goal is to uncover the pathophysiology of PSP and the molecular substrates of its subtypes that will ultimately lead to drug discoveries.

Using genome-wide genotypes, brain gene expression and DNA methylation measures, the team identified gene expression changes associated with PSP risk variants previously nominated by disease GWAS, importantly nominating the likely influenced gene at these loci. These findings were further characterized by assessment with DNA methylation and neuropathology, providing insights into the mechanism of action and neuropathological feature most associated with these variants. Brain transcriptome measures were also assessed for association with the different neuropathological features of PSP; the findings implicate novel genes and pathways in this disease and identify divergent patterns of association with neuronal (NFT) and astrocytic (TA) pathology. Current studies are aimed at expanding these initial findings to additional samples and multiomics measurements.

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