Defining isoform diversity conserved in the brain and blood, related to the severity of Prader-Willi syndrome

Funding Summary

Dr. Godler has been investigating cell-specific changes in gene expression in blood and brain tissue samples from individuals with PWS, with the goal of developing blood-based biomarkers of PWS severity.  Here his collaborative will apply newer technologies to look at genes and proteins that are differentially expressed in PWS and use that knowledge to query databases to identify drugs that may be ‘repurposed’ to treat PWS. 

Lay Abstract

For people with PWS, their families, and the medical professionals caring for them, the pressing needs are identification of early clinical and/or biological predictors of symptoms including serious mental illness and constant hunger that may be targeted with specific treatments. The underlying biological mechanisms in key areas of the human brain, linked to these phenotypes, have also not been comprehensively studied. This project aims to define biological mechanisms in blood and brain underlying key symptoms of PWS to address these needs. It will bring together an interdisciplinary team of investigators with an outstanding record in the field, established state-of-the-art technologies, deep clinical expertise and access to the world’s largest collection of post-mortem brain tissues from individuals with PWS.
In our previous FPWR funded studies we identified 53 genes, responsible for functions of ribosomes or small components in each cell to be upregulated in different types of cells in brains of donors with PWS. There are many ribosomes in each cell with each involved in the process of making different proteins coded by the genes. Proteins are large, complex molecules that play many critical roles in the body. Each gene can produce many different proteins which depends on how this message is read by each cell. This protein specific message is known as an isoform. Of all the genes examined, we have found only one ribosomal gene called RPS18 (that contributes to important functions of the ribosome involved in protein production) to be upregulated in all types of cells in specific regions of the brain from donors with PWS. We then showed that this upregulation in blood was associated with severity of PWS in another group of living individuals, including intellectual functioning and behavioral problems. While these changes and related functions of the ribosome in making different isoforms have been previously implicated in autism, this is the first time they will be studied in the brain of donors and their levels related to severity of PWS.
In this project we will analyze this rich dataset from different regions of the brain with different functions to help us understand how abnormal activity of ribosomes influences expression of unique isoforms of proteins from the same genes in different types of cells. Our previous study findings suggest that we should focus on brain immune cells (glial cells) which support the proper functioning of neurons in the brain. Once we collect this valuable information, we plan to use it as part of a competitive renewal application in the second year of this project to determine how these changes are related to behavioral issues and other key clinical features seen in PWS. We will also use artificial intelligence to identify treatments from global drug databases, to target specific pathways, isoforms and proteins identified to be dysregulated in blood and brain tissues in different types of cells and relationships to severity in PWS. Together these will: (i) define genetic pathways dysregulated in PWS blood and brain cells of clinical significance, and (ii) identify existing medications used for other conditions.