Gene expression studies in progressive supranuclear palsy
Progressive supranuclear palsy is a rapidly progressive neurodegenerative disorder with clinicopathologic heterogeneity and without any therapies.
A progressive supranuclear palsy genome-wide association study 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 the identification of the disease gene, the functional variants and their mechanism of action. These goals cannot be achieved by the disease genome-wide association study alone. Alternative, powerful and mechanistic approaches are required.
Dr. Ertekin-Taner's lab leads a project that aims to close this knowledge gap by integrative analysis of multi-omics measures (transcriptome, genetics and epigenomics data) with quantitative neuropathology. In collaboration with Dennis W. Dickson, M.D., director of the Mayo Clinic Brain Bank, the team is using brain samples from autopsied progressive supranuclear palsy subjects with neuropathology measures for these tau pathological features of progressive supranuclear palsy:
- Neurofibrillary tangles.
- Tufted astrocytes.
- Tau threads.
- Coiled bodies.
The long-term goal is to uncover the pathophysiology of progressive supranuclear palsy 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 progressive supranuclear palsy risk variants previously nominated by disease genome-wide association study, 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 neuropathologic features most associated with these variants.
Brain transcriptome measures also were assessed for association with the different neuropathologic features of progressive supranuclear palsy. The findings implicate novel genes and pathways in this disease and identify divergent patterns of association with neuronal (neurofibrillary tangles) and astrocytic (tufted astrocytes) pathology. Studies aim to expand these initial findings to additional samples and multi-omics measurements.
Related publication
- Allen M, Wang X, Serie DJ, Strickland SL, Burgess JD, Koga S, Younkin CS, Nguyen TT, Malphrus KG, Lincoln SJ, Alamprese M, Zhu K, Chang R, Carrasquillo MM, Kouri N, Murray ME, Reddy JS, Funk C, Price ND, Golde TE, Younkin SG, Asmann YW, Crook JE, Dickson DW, Ertekin-Taner N. Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy. Acta Neuropathologica. 2018.
- Allen M, Burgess JD, Ballard T, Serie D, Wang X, Younkin CS, Sun Z, Kouri N, Baheti S, Wang C, Carrasquillo MM, Nguyen T, Lincoln S, Malphrus K, Murray M, Golde T, Price ND, Younkin SG, Schellenberg GD, Asmann Y, Ordog T, Crook J, Dickson D, Ertekin-Taner N. Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci. Acta Neuropathologica. 2016.