Dr. Godler’s lab is interested in identifying early predictors of autism and serious mental illness in PWS. In their preliminary data, they have found that inflammatory pathways linked to UBE3A (a key gene that regulates normal brain development and immune cell function) were affected differently in PWS caused by uniparental disomy (UPD), compared to deletion PWS. This study will extend that data, examining how UBE3A activity and the related immune cell inflammatory pathways affect behavioral issues in children and adolescents with PWS, comparing deletion and non-deletion PWS.
Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.
Mental health problems, including psychosis, are debilitating issues that are experienced by a significant number of individuals with PWS. Therefore, one of the pressing needs for people affected with PWS, their families and the medical professionals caring for them, is identification of early predictors (clinical and/or biological) of serious mental illness. This is important because it can enable prevention strategies for those at risk and targeted early treatment for those who experience mental illness. Research from other fields has shown that there is a strong link between autism features and early predictors of mental health issues including psychosis. However, this has not been comprehensively investigated in individuals with PWS, particularly in individuals with PWS due to maternal uniparental disomy (matUPD), who are especially vulnerable to both psychosis and autism features. Increased expression of UBE3A, a key gene that regulates normal brain development and function, has been closely linked to autism in other disorders. However, this increased expression and the biological inflammatory pathways that may be impaired due to increased activity of UBE3A has not been comprehensively investigated in PWS.
Using state-of-the-art laboratory methods (single cell RNA sequencing and droplet digital PCR), we uncovered intriguing preliminary data on 22 Australian PWS individuals. In non-deletion PWS (most matUPD) increased UBE3A levels in white blood cells were linked to more severe autism features, but not issues with intellectual functioning. The data also suggested that inflammatory pathways linked to UBE3A in cells of the immune system and that these pathways were affected differently in non-deletion PWS, compared to deletion PWS.
This study will extend on our preliminary data examining how UBE3A activity and the related immune cell inflammatory pathways affect behavioral issues in children and adolescents (<19 years) with PWS (also comparing deletion and non-deletion PWS). We will test immune cells from blood samples from previous study participants and new participants recruited into the study making up a total of 60 children and adolescents (20 deletion and 40 non-deletion; equal split between AUS/USA). All participants will undergo formal clinical and psychological assessments. In addition, we will also examine if and how the genetic findings from blood may be linked to genetic changes in the related brain immune cells (glial cells) which support the proper functioning of neurons in a region of the brain called cortex. The study will use tissues from 6 donated brains from people with PWS (both deletion and non-deletion) and 6 matched controls collected by previous studies.
This study will lead to a better understanding of how UBE3A activity and associated inflammatory pathways in blood and brain are associated with important clinical features of PWS, namely autism and psychotic features. The goal is to enable evidence-based choice of currently available treatments, and to identify pathways that can be specifically targeted in future clinical trials with anti-inflammatory medications currently in use for other conditions.
David Godler, PhD
Murdoch Children's Research Institute