Defining Cell-Type Specific Signatures and Dysregulated Pathways from Blood and Brain in PWS (Year 2)

Funding Summary

In year 1 of this project we found increased UBE3A levels in white blood cells was linked to more severe autism features, but only in non-deletion PWS (most matUPD). In year 2, we will analyze the dataset created in year 1 to help us understand how activity of UBE3A and other key genes (related to inflammatory and other dysregulated pathways) influence expression of behavioral issues and other key clinical features in PWS. We will examine if and how the genetic findings from blood may be specifically linked to genetic changes in the related brain immune cells (glial cells) which support the proper functioning of neurons in cortex and hypothalamus. Together these will: (i) define genetic pathways dysregulated in PWS blood and brain, and (ii) identify existing medications used for other conditions to target these pathways in future PWS clinical trials to address the needs of people with PWS, their families, and the clinicians caring for them.

Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip. 

Lay Abstract

For people with PWS, their families, and the medical professionals caring for them, the pressing needs are identification of early predictors (clinical and/or biological) of symptoms including serious mental illness that may be targeted with specific treatments. To date, this has not been comprehensively investigated particularly in individuals with PWS due to maternal uniparental disomy (matUPD), who are especially vulnerable to both psychosis and autism features. The underlying biological mechanisms in key areas of the human brain, linked to these phenotypes, have also not been comprehensively studied.

This project is the 2nd year renewal aimed at characterizing 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 year 1 we found increased UBE3A levels in white blood cells was linked to more severe autism features, but only in non-deletion PWS (most matUPD) (Baker et al. Godler 2020 Translational Psychiatry 10:362). We also analyzed brain tissues from 15 PWS and 39 typically developing individuals and processed 8 PWS (4 deletion and 4 non-deletion) and 4 control brain samples using a state-of-the-art single nucleus RNA sequencing technology. This provided information about the activity of most genes in the human body (transcriptome) at unparalleled resolution in different types of cells of the brain, and confirmed that UBE3A expression was significantly elevated in the brain tissues, but only in the non-neuronal cell types, and only in the non-deletion subtypes. The non-deletion brain tissues also showed significant dysregulation of specific inflammatory pathways (e.g. neutrophil degranulation). While these pathways have been previously implicated in autism, this is the first time they have been identified to be dysregulated in PWS non-deletion brain tissues.

In year 2, we will analyze this rich dataset to help us understand how activity of UBE3A and other key genes (related to inflammatory and other dysregulated pathways) influence expression of behavioral issues and other key clinical features in PWS. We will examine if and how the genetic findings from blood may be specifically linked to genetic changes in the related brain immune cells (glial cells) which support the proper functioning of neurons in cortex and hypothalamus. We will use artificial intelligence to identify treatments from global drug databases, to target specific pathways identified to be dysregulated in blood and brain tissues in different types of cells. Together these will: (i) define genetic pathways dysregulated in PWS blood and brain, and (ii) identify existing medications used for other conditions to target these pathways in future PWS clinical trials to address the needs of people with PWS, their families, and the clinicians caring for them.