Job Opportunities

SWAN PhD Studentship 2008, Royal Holloway University of London, UK

Exploring the role of dopamine receptor interacting proteins in psychiatric disorders using Dictyostelium as a model organism

Summary:
Schizophrenia and bipolar disorder are common neuropsychiatric conditions causing great personal and societal costs. Both disorders have a strong genetic component and may share a common disease-causing mechanism. The identities of the causative genes remain unknown, and few model systems allow in-depth research into cell signalling changes associated with the disorders. One pathway implicated in both disorders is that regulated by the neurotransmitter dopamine, which controls both cognitive and motor aspects of brain function. In pursuit of a better understanding of the dopamine signalling pathway, research in Dr Nasir's laboratory has recently identified eleven novel dopamine receptor interacting proteins (DRIPs) in mammalian systems. A greater understanding of the cellular and molecular role of these proteins may help to unravel the complex basis of neuropsychiatric conditions such as schizophrenia and bipolar disorder.

This project will employ a simple biomedical model, Dictyostelium discoideum, to better understand the role of DRIPs in cellular function. The model has many signalling pathways common to mammalian systems, and a number of DRIP homologues and a single potential Dopamine receptor - suggesting it can also be used to study the dopamine signalling pathway. Research by Dr Williams's group has centred on understanding signalling pathways potentially involved in bipolar disorder using Dictyostelium as a model. This current research project, based at Royal Holloway, will examine the role of DRIPs in Dictyostelium cell signalling, by generating DRIP knockouts in stable isogenic lines, and analysing the cellular role of each protein. The project will also asses the effect of current bipolar disorder drug treatments on these knockout strains. This research may provide valuable advances in our understanding of psychiatric disorders including schizophrenia and bipolar disorder.

For further reading see:

1. Nan, Hou, Maclean, Nasir, Lafuente, Shu, Kriaucionis and Bird (2007) Interaction between chromatin proteins MeCP2 and ATRX is disrupted by mutations that cause inherited mental retardation. PNAS 104 (8) 2709-2714
2. Williams, Boeckeler, Graf, Muller-Taubenberger, Li, Isberg, Wessels, Soll, Alexander, and Alexander (2006) Towards a molecular understanding of human diseases using Dictyostelium discoideum. Trends Mol Med, 12, 415-424.
3. Eickholt, Towers, Ryves, Eikel, Adley, Ylinen, Chadborn, Harwood, Nau and Williams (2005) Effects of valproic acid derivatives on inositol trisphosphate depletion, teratogenicity, GSK-3β inhibition and viral replication - A screening approach for new bipolar disorder drugs based on the valproic acid core structure. Mol Pharm, 67, 1-8
4. Williams (2005) Pharmacogenetics in model systems: Defining a common mechanism of action for mood stabilisers. Progress in Neuro-psychopharmacology and Biological Psychiatry, 29, 1029-1037.
5. Sperandio, Poksay, de Belle, Lafuente, Liu, Nasir* and Bredesen* (2004) Paraptosis: mediation by MAP kinases and inhibition by AIP-1/Alix. Cell Death Different 11 (10), 1066-1075. * Joint senior authors

(posted February 25, 2008)

PhD studentship, Royal Holloway University of London, UK

Understanding presenilin-controlled cell signalling in a basic biomedical model

Studies into Alzheimer's disease (AD) pathogenesis have employed familial AD patients, who inherit mutations in two Presenilin (PS) genes, giving rise to the pathogenic basis of the disease. Numerous mutations in these PS proteins have been discovered, but understanding the common effects of these mutations has been difficult. This project will employ a simple biomedical model, Dictyostelium, to analyse the role of PS proteins (and associated AD-inducing mutations) in cellular function. We will also analyse the common effects of therapeutic drugs on cell signalling changes induced by PS mutations. This work will provide a novel and potentially highly productive mechanism for analysing AD pathology with the possibility of identifying novel AD treatments.

Funding covers full fees for UK/EU students and a student stipend.

For further reading see:

• Cowburn, Popescu, Ankarcronaa, Dehvaria and Cedazo-Mingueza (2007) Presenilin-mediated signal transduction. Physiol Behav 92, 93-7.
• De Strooper (2007) Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep 8, 141-6.
• Czech, Tremp and Pradier (2000) Presenilins and Alzheimer's disease: biological functions and pathogenic mechanisms. Prog Neurobiol.60:363-84.
• Williams, Boeckeler, Graf, Muller-Taubenberger, Li, Isberg, Wessels, Soll, Alexander, and Alexander (2006) Towards a molecular understanding of human diseases using Dictyostelium discoideum. Trends Mol Med, 12, 415-424.
• Williams (2005) Pharmacogenetics in model systems: Defining a common mechanism of action for mood stabilisers. Progress in Neuro-psychopharmacology and Biological Psychiatry, 29, 1029-1037.
• Malik, Currais, Andres, Towlson, Pitsi, Nunes, Niblock, Cooper, Hortobágyi, Soriano (2007) Loss of neuronal cell cycle control as a mechanism of neurodegeneration in the Presenilin-1 Alzheimer's disease brain Cell Cycle. Online only.

(posted February 8, 2008)

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