Funding Summary
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.
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Lay Abstract
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.
Research Outcomes: Public Summary
Mental health problems, including psychosis, are debilitating issues experienced by a significant number of individuals with PWS. 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 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.
In year 1 of this project, we used state-of-the-art laboratory methods (single cell RNA sequencing and droplet digital PCR), to uncovered intriguing preliminary data from 27 PWS and 20 typically developing control 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 (Baker et al. Godler 2020 Translational Psychiatry 10:362). These data also suggested that inflammatory pathways were linked to UBE3A and 12 other key genes in cells of the immune system and that the pathways they regulate were affected differently in non-deletion PWS, compared to deletion PWS (publications in preparation). At the end of year 1 we recruited and collected immune cells from blood samples of 38 study participants with PWS (24 non-deletion and 14 deletion). All participants underwent formal clinical and psychological assessments. We also analyzed brain tissues from 15 PWS and 39 typically developing individuals to select 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 activity of most genes in the human body (transcriptome) at unparalleled resolution in different cells of the brain.
Research Outcomes: Publications
Relationships between UBE3A and SNORD116 expression and features of autism in chromosome 15 imprinting disorders. Baker EK, Butler MG, Hartin SN, Ling L, Bui M, Francis D, Rogers C, Field MJ, Slee J, Gamage D, Amor DJ, and Godler DE. Translational Psychiatry. https://doi.org/10.1038/s41398-020-01034-7