Scientists identify potential therapeutic targets for progressive supranuclear palsy

Robust gene expression research in humans, mice, and fruit flies has revealed three potential drug targets for progressive supranuclear palsy (PSP). Scientists used systems biology approaches - methods of studying how all the parts of a living organism work together - to identify potential therapeutic strategies based on changes in gene expression in specific types of brain cells. Results from the NIA-funded study were published in Nature Communications.

PSP is a neurodegenerative disorder that causes movement symptoms, including serious problems with walking, balance, eye motion, and swallowing. Symptoms worsen over time and often cause life-threatening complications. Currently, there is no cure for the disorder.

Genes are pieces of DNA in our genome that contain instructions for molecules that do the work of the cell. The genes in our DNA are transcribed into a go-between molecule called RNA. The cell then reads the RNA and produces the protein encoded by that gene. This process is called gene expression. Messenger RNA (mRNA) carries instructions from your DNA to the parts of the cell that make proteins. Scientists look at how different diseases affect gene expression by measuring the amount of mRNA present for each gene. Previous studies examined differences in gene expression in the brains of people with and without PSP. These studies, however, did not focus on whether these differences in gene expression were consistent among the different types of cells in the brain.

Brains contain many different types of cells. Neurons transmit information via chemical and electrical signals. Several other types of cells, collectively called glial cells, support the neurons by nourishing them, clearing waste, and fighting invaders. Gene expression experiments that do not take cell type into account can lose important information. To address this gap in knowledge, a group of scientists from Mayo Clinic, University of Kentucky, and Emory University looked at cell-specific changes in gene expression in postmortem brains from people with and without PSP.

The researchers used sophisticated molecular biology techniques to examine how PSP changes gene expression in specific cell types in the brain. They generated a list of genes that had increased or decreased expression in PSP brains compared with brains from people without the disorder. Many of these gene expression changes were found in glial cells. The scientists repeated the gene expression experiments in two animal models of PSP, mouse and fruit fly. Combined, these experiments and analyses discovered three genes - DDR2, STOM, and KANK2 - as possible therapeutic targets.

This study strongly supports a model in which PSP causes changes in the expression of the DDR2, STOM, and KANK2 genes in glial cells in the brain. Results were consistent across three different species, which increases the confidence that targeting these genes with drugs may be an effective therapeutic strategy. The researchers also uploaded their data into an interactive online tool. Future research may include using this tool to explore how PSP changes the expression of any gene studied in humans, mice, or fruit flies. Overall, the study presents a robust experimental plan to find therapeutic targets for disease and paves the way for future studies that aim to develop treatments for PSP.

Reference: Min Y, et al. Cross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy. Nature Communications. 2023;14(1):6801. doi: 10.1038/s41467-023-42626-3.