Gene Expression Studies In Progressive Supranuclear Palsy
Progressive supranuclear palsy (PSP) is a rapidly progressive neurodegenerative disorder with clinicopathologic heterogeneity and without any therapies. Genetic studies can be instrumental in identifying the molecular pathophysiology underlying PSP risk and its heterogeneity, which may enable discovery of therapeutic targets.
Until recently, the H1 haplotype of the tau gene (MAPT) was the strongest genetic risk factor for PSP. However, a new PSP genome-wide association study (GWAS) identified six additional loci. 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.
This project aims to close this knowledge gap by joint analysis of the whole transcriptome and quantitative neuropathology measures in a well-characterized autopsied PSP cohort with existing GWAS data. 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. Given the clinicopathological overlap between PSP and other tauopathies, the proposal is expected to impact a wide range of neurodegenerative disorders and generate novel therapeutic avenues.
The central hypothesis of the lab is that many PSP variants confer risk by regulating brain gene expression. Further, differential transcriptional regulation may underlie the heterogeneity in PSP. Preliminary data has identified brain transcript associations for some of the top PSP GWAS variants supporting this hypothesis.
Through collaborations with the brain bank at Mayo Clinic and Dennis W. Dickson, M.D., the team has access to nearly 500 brain samples from autopsied PSP subjects with existing GWAS approximately 400 have typical and approximately 100 have atypical clinicopathology). All subjects have clinical data and detailed quantitative neuropathology measures. The objective is to obtain brain transcriptome measurements in this unique cohort, which will be analyzed jointly with quantitative neuropathology measures.
The goal of this project is to identify functional variants underlying PSP risk, its clinicopathological heterogeneity and to discover the mechanism of action of these variants.
The expected outcomes include:
- Identifying genetic variants that influence gene expression in PSP brains and transcript level differences between subtypes of PSP that are not due simply to aging
- Discovering genetic factors that influence both neuropathology and gene expression in PSP, as well as transcripts that correlate with neuropathology
- Uncovering the mechanism of transcriptional regulation in PSP by next-generation RNA sequencing of 200 select PSP brain samples and obtain translational in vitro studies
Results from all aims will be compared with the PSP disease GWAS. The overall knowledge will nominate genes and their transcriptional changes as novel disease mechanisms in PSP. These molecular mechanisms will constitute modifiable drug targets that impact PSP and other related neurodegenerative diseases.