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Contact Details Department of Biology (Area 9) University of York PO Box 373 York YO10 5YW Tel: +44 (0)1904 328537 E-mail: sts1@york.ac.uk Office: B/L020

Career Outline

1987	BSc	Staffordshire University
1991	MPhil	University of Leicester
1996	PhD	University of Cambridge
1996-1999	Post-doc	University of Cambridge
2000-2004	Post-doc	University of California, San Francisco
2004-	Lecturer	University of York

Research Interests

My research centres on the role of the endosome in regulating signals controlling synapse growth. Appropriate regulation of synaptic growth is a key mechanism in regulating the fidelity of synaptic communication. Many neurodegenerative diseases show abnormal function of endosomal compartments. My previous work has suggested that in one form of neurodegenerative disease, a lysosomal storage disorder, endosomal perturbation leads to an excessive growth of the synapse most likely due to the failure to regulate growth signals appropriately. Working with the larval neuromuscular junction of Drosophila as a model synapse, I will model the lysosomal storage diseases to further understand the cellular perturbations that give rise to the profound neurodegeneration produced by this set of devastating genetic conditions.

Discoveries:
Identification of the endosomal protein spinster as a key regulator of synapse growth and function. Identification of other key membrane trafficking steps essential to synaptic transmission and growth such n-synaptobrevin, and Dap160. I have also developed key tools in common use for the silencing of synapses in Drosophila.

Some Recent Publications

Sweeney ST and Davis GW (2002) Unrestricted growth in spinster: regulation of synapse development from an endosomal/lysosomal compartment. Neuron 36: 403-416

Sanyal S and Ramaswami M (2002) Spinsters, synaptic defects, and amaurotic idiocy. Neuron 36: 335-8

Marie, B., Sweeney, S.T., Poskanzer, K.E., Roos, J., Kelly, R.B. and Davis, G.W. ( (2004) Dap160/Intersectin Scaffolds the Peri-Active Zone to Achieve High-Fidelity Endocytosis and Normal Synaptic Growth Neuron 43: 207-219

Current Research Projects

• Oxidative stress and the regulation of synapse function
  Funding body: BBSRC
• Modelling sphingolipidosis neurodegeneration in Drosophila.
  Funding body: BBSRC
• A Drosophila model of a human sensory neuropathy
  Funding body: MRC

Professional Activities

• Editorial board member for Intertebrate Neuroscience
• Member of the Biochemical Society

PhD Research Projects Available for 2010

Structural biochemistry and physiology of the axonal guidance protein Scribbler from Drosophila (for 2010-11)
Description: Neurodegenerative diseases are a set of pathological conditions resulting in the slow and irreversible loss of regions of the brain and/or spinal cord. Many neurodegenerative diseases are proteinopathies associated with protein misfolding or innappropriate protein aggregation. A large number of proteins linked to neurodegenerative conditions are intrinsically disordered, i.e. they lack stable tertiary or secondary structure under physiological conditions. The spinocerebrellar degeneration observed in Dentatorubral-Pallidoluysian atrophy (DRPLA) arises from an expanded CAG triplet repeat in the protein atrophin-1. In Drosophila, Atrophin-1 interacts physically with the intrinsically disordered transcriptional repressor Scribbler to regulate embryonic development and axonal guidance. The aim of this project is to combine in vivo experimentation using Drosophila with in vitro biochemical, biophysical and structural analysis of the Scribbler protein and its interactions with Atrophin-1 to understand the underlying basis for this critical association and if repeat expansion in atrophin-1 affects their association. This project is in collaboration with Prof Colin Kleanthous and Dr Jennifer Potts in York.

Identifying novel factors involved in Frontotemporal Dementia (for 2010-11)
In collaboration with Dr Fen-Biao Gao of the Gladstone Institute for Neurology in San Francisco, we have developed a Drosophila model of Frontotemporal Dementia (FTD) based on the autosomal dominant mutations in the membrane trafficking protein CHMP2B identified in a Danish family pedigree. Using this model we have identified the Toll pathway as a regulator of the neurodegenerative process (Ahmad et al., 2009 PNAS in press). We will exploit our model further to determine the cellular role of the Toll pathway in synapse and dendrite dysfunction. Using the advanced genetics of Drosophila, we will also identify additional factors that increase or decrease the extent of neurodegeneration in our model of FTD. Using this model, we will build up a molecular and cellular description of the events underlying FTD.

Lab Members

Status	Name	Project
PhD Student	Matthew Oswald	Drosophila as a model of Sensory Neuropathy
PhD Student	Valerie Milton	Oxidative Stress, synapse growth and function
PhD Student	Samantha Hindle	Saposin Deficiency in Drosophila, a model for Lysosomal storage Disease