Edinburgh Research Explorer

Biography

I trained in biochemistry at the University of Edinburgh then went on to do a PhD studying DNA ligase I with Prof David Melton, one of the leaders in the field of gene targeting. After a short period of post-doctoral training at the MRC Reproductive Sciences Unit, I joined Professor David Porteous at the MRC Human Genetics Unit in 1995, followed by a move to the University of Edinburgh in 2000, to study a unique Scottish family in which a balanced t(1;11) chromosomal translocation substantially increases risk of schizophrenia, bipolar disorder and depression. This family has been a major focus of my work since 1995. 

Through study of this family I identified the gene Disrupted In Schizophrenia 1 (DISC1) as a potential risk factor for major mental illness because it is directly disrupted by the  translocation. In addition to the translocation, a number of genetic variants have been identified that alter the DISC1 protein sequence and potentially influence the risk of developing a psychiatric disorder.

I am working towards increased understanding of the molecular pathways that underlie major mental illness, with the aim of eventually identifying and testing drug targets and small molecules that regulate these pathways. DISC1 controls  important brain processes, such as generation of neurons and neuronal signalling, but the mechanisms by which it does so are not fully understood. To investigate this I am studying a key subset of DISC1 interactors including the cAMP phosphodiesterase PDE4 that regulates cAMP signalling, the kinase GSK3b that regulates multiple signalling pathways, and the trafficking molecules NDE1 and NDEL1.  All of these proteins are essential for important aspects of brain development and function.  Moreover PDE4 and NDE1 have been independently implicated as potential risk factors for major mental illness, while GSK3b is a target of Lithium, used to treat mood disorders. I am using a variety of model systems to study the consequences of altered DISC1 expression or DISC1 sequence variants for neuronal function to identify mechanisms that may be dysfunctional in psychiatric patients.

My work points to deficits in cAMP signalling and in intracellular trafficking, including mitochondrial dynamics, as potential contributory factors in mental illness. I am studying these, and other aspects of DISC1 function, in induced pluripotent stem cell-derived neurons originating from psychiatric patients carrying chromosomal anomalies including the t(1;11) translocation. These cells are being generated through the generosity of psychiatric patients and their families, and in collaboration with Professors Douglas Blackwood, Andrew McIntosh and Siddharthan Chandran at the University of Edinburgh.

Qualifications

PhD in molecular biology awarded 1994 at the University of Edinburgh

BSc: 1st class honours biochemistry awarded 1990 at the University of Edinburgh

Current Research Interests

molecular mechanisms influencing risk of major mental illness

Research Interests

We want to understand the molecular pathways that underlie major mental illness, with the aim of eventually identifying and testing drug targets and small molecules that regulate these pathways. We are focussing upon DISC1, which we identified as a putative genetic risk factor for major mental illness. The DISC1 gene is directly disrupted by a chromosomal t(1;11) translocation, inheritance of which substantially increases risk of schizophrenia, bipolar disorder and major depressive disorder in a large Scottish family. In addition to the translocation, a number of genetic variants have been identified that alter the DISC1 protein sequence and potentially increase disease risk.

DISC1 regulates important brain processes, such as generation of neurons and neuronal signalling, but the mechanisms by which it does so are not fully understood. To investigate this we are studying a key subset of DISC1 interactors including the cAMP phosphodiesterase PDE4 that regulates cAMP signalling, the kinase GSK3beta that regulates multiple signalling pathways, and the trafficking molecules NDE1 and NDEL1.  All of these proteins are essential for important aspects of brain development and function. Moreover PDE4 and NDE1 have been independently implicated as potential risk factors for major mental illness, while GSK3beta is a target of Lithium, used to treat mood disorders. We are using a variety of model systems to study the consequences of altered DISC1 expression or DISC1 sequence variants for neuronal function to identify mechanisms that may be dysfunctional in psychiatric patients.

Our work points to deficits in cAMP signalling and in intracellular trafficking, including mitochondrial dynamics, as potential contributory factors in mental illness. We are studying these, and other aspects of DISC1 function, in induced pluripotent stem cell-derived neurons originating from psychiatric patients carrying chromosomal anomalies including the t(1;11) translocation. These cells are being generated through the generosity of psychiatric patients and their families, and in collaboration with Professors Douglas Blackwood, Andrew McIntosh and Siddharthan Chandran.

My research in a nutshell

Our research is aimed at identifying what happens in the brain to predispose certain people to develop a major mental disorder (schizophrenia, bipolar disorder or recurrent major depressive disorder). It is well established that genetic inheritance strongly influences the chances of developing a major mental illness, and consequently we are studying the brain functions of genetic risk factors for major mental illness in order to understand disease mechanisms. We are focussing upon a gene called DISC1 because it is damaged by a chromosomal rearrangement (a translocation) that substantially increases the chances of developing schizophrenia, bipolar disorder or recurrent major depressive disorder in translocation carriers in a large family from Scotland. The protein product of this gene is known to be important for many aspects of brain development and function, and we aim to understand the mechanisms by which DISC1 regulates these processes, and how these mechanisms may be defective in psychiatric patients.

The DISC1 protein works together with several other proteins to perform its roles in the brain, including proteins specified by genes which are themselves potential genetic risk factors for major mental illness. We are investigating functions carried out by DISC1, together with a number of such proteins. One, called PDE4, acts together with DISC1 to control the amount of cAMP present within cells. cAMP is an important signalling molecule that specifies whether many cell functions are switched on or off, and we are investigating which of these cAMP-dependent functions, controlled by DISC1 and PDE4, may be defective in psychiatric patients, perhaps due to incorrect cAMP levels. We have also shown that DISC1 controls movement of mitochondria around neurons. Mitochondria are the ‘powerhouses’ of cells, providing the energy that is required to power most cellular functions. Proper brain function is critically dependent upon neurons being able to communicate with each other, and this process is powered by mitochondria which must be efficiently moved to the part of the neuron where they are required. Because neurons are extremely long and thin they are particularly sensitive to inefficient mitochondrial transport, and may be unable to communicate effectively as a result. We are investigating whether defective mitochondrial transport in neurons could increase the chances of developing a mental illness.

We are ‘reprogramming’ skin cells from psychiatric patients and their unaffected relatives to generate neurons ‘in a dish’ to use in our studies. These neurons will enable us to determine whether the processes we have identified as potentially of importance are defective in neural material derived from individuals carrying damaged copies of the genes we are studying. In this way we aim to identify brain mechanisms that influence the chances of developing a severe psychiatric disorder. We are grateful for the generosity of the people who have donated skin biopsies, without which we would be unable to access the neural material that is essential for this work.

Teaching

BSc Honours neuroscience  ' neurogenetics':  course organiser and lecturer

MSc Genetics and Disease: lecturer

MSc Quantitative Genetics and Genome Analysis: lecturer

Highlighted research outputs

  1. DISC1, PDE4B, and NDE1 at the centrosome and synapse

    Research output: Contribution to journalArticle

  2. Behavioral phenotypes of Disc1 missense mutations in mice

    Research output: Contribution to journalArticle

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