Oligodendroglial isoforms of ANK3 and their role in the etiology of bipolar disorder

Bipolar disorder is a severe mental disorder affecting 1% of population and is classified as a top disorder of morbidity and lost productivity by the World Health Organisation. The reason for this high health and social burden is the early age of onset which means that patients suffer from the disease for most of their life. In this project, we aim to understand the biological mechanism through which one major genetic risk factor for bipolar disorder (expression of the ANK3 gene) contributes to the patients' symptoms. We have identified a specific protein product of the ANK3 gene that is clearly over-expressed in patients and, thus, made a first step in understanding the disease mechanism. In this project, we will push this research further and determine the function of this specific ANK3 protein, in what cell type it is expressed, where in the cell it is located, and what happens to the brain cells when a higher than normal amount of the protein is produced. Identification of the molecular components which drive the disorder has the potential to have a substantial impact on public health costs and the quality of life of patients: 1. A cellular phenotype will help both patients and researchers to understand the disease mechanism and its link to the behavioural phenotype 2. Psychiatrists will have the opportunity to begin using biological criteria in diagnosis and these biological criteria may help identify distinct subtypes of the disorder 3. An understanding of the fundamental genetic drivers of neuro-psychiatric disorders is a key prerequisite for the development of better drug treatments

The objective of this project is to understand the causes of bipolar disorder (BD). Although variation in 30 genes has been shown to be associated with the disorder, little is know about the mechanisms through which these genes lead to the symptoms of mania and depression. We have identified a specific protein product of the ANK3 gene that is clearly over-expressed in patients and, thus, made a first step in understanding the disease mechanism. It is important to push this research further and determine the function of this specific ANK3 protein, in what cell type it is expressed, where in the cell it is located, and what happens to the cells when a higher than normal amount of the protein is produced. The technical challenges include: working with novel single cell sequencing technologies, generating a mouse model with overexpression of this very long protein, and detecting the protein product in ultramicroscopic structures. We are proposing a Houston-Oslo team that is well qualified to successfully overcome these challenges and substantially advance our understanding of ANK3’s role in BD. Such an advance has the potential to accelerate the discovery of the mechanims by which some of the other 29 genes are associated with the disorder. User benefits include helping patients understand the disease and providing psychiatrists with the opportunity to employ biological criteria in diagnosis. Most importantly, an understanding of the fundamental molecular drivers of neuro-psychiatric disorders will inform drug development. For more than 60 years, lithium has remained the first-line treatment for prevention of manic and depressive episodes of BD, despite its mechanism of action being at best only partially understood. Moreover, only 30 percent of BD patients are lithium responders and the treatment has a number of side-effects (including weight gain, hand tremor, risk of kidney damage). An understanding of BD pathobiology will create a platform for improving treatment.