Dr Sean T Sweeney
Lecturer

Profile

Career

2004 - Lecturer Department of Biology, University of York
2000 - 2004 Wellcome Trust Prize Travelling Fellow University of California, San Francisco
1996 - 1999 Darwin College Research Fellow University of Cambridge
1996 PhD University of Cambridge
1991 MPhil University of Leicester
1987 BSc Staffordshire University   

Research

Overview

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. We work with the larval neuromuscular junction of Drosophila as a model glutamatergic synapse to identify endosomal related signaling events occurring in human pathological conditions.

Many neurodegenerative diseases show abnormal function of endosomal compartments. My previous work has suggested that in one form of neurodegenerative disease, a childhood dementia, endosomal perturbation leads to an excessive growth of the synapse most likely due to the failure to regulate growth signals appropriately. Using this model we have identified oxidative stress as a major signal driving synapse overgrowth.

We also study a form of Frontotemporal Dementia (FTD) that  has a perturbed endosome. We have used our Drosophila model of FTD to identify factors regulating progression of the disease and we are now building up a picture of the cellular events happening in synapses when they are affected by this condition.

Discoveries

Development (with Dr Cahir O’Kane, Cambridge, Prof Richard Baines, Manchester) of key tools for selectively silencing neurons in the Drosophila brain. These tools have become the ‘go-to’ tool for silencing synapses and have also been developed for us in mouse and zebrafish models.

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.

In recent work we have identified oxidative stress as a regulator of synapse growth. A potentially critical insight into the signalling activated in the brain both during ageing and neurodegenerative disease.

Development of a Drosophila model of Frontotemporal Dementia that is effectively identifying factors involved in disease progression.

Current projects

  • Oxidative stress and the regulation of synapse function (Funding body: BBSRC, 1/08/11 to 31/07/14)
  • A Drosophila model of Frontotemporal Dementia (Alzheimer’s Society)
  • The effect of free radicals on synaptic function and connectivity within individual neuronal connections and neuronal circuits (Funding body: C2D2, 1/3/13 to 31/1/14

Research group(s)

StatusNameProject
PhD Student Ryan West
(Alzheimer’s Society Studentship)
Oxidative Stress, synapse growth and function
BBSRC DTP student

Nathan Garnham

Identifying signalling responses governing synapse growth and function in ageing neurons: Defining responses to different cellular sources of oxidative stress
Post-Doc

Annika Rings
(joint supervision with Prof. Miles Whittington)

The effect of free radicals on synaptic function and connectivity within individual neuronal connections and neuronal circuits

Lab Alumni

  • Laura Briggs (post-doc) Schoolteacher
  • Matthew Oswald (PhD student) Post-Doc in lab of Dr Matthias Landgraf, Department of Zoology, University of Cambridge
  • Samantha Hindle (PhD student) Post-Doc in lab of Dr Roland Bainton, Department of Anesthesia, University of California, San Francisco
  • Valerie Milton (PhD student) Postgraduate Medical student, Queen Mary’s University, London

 

Collaborators

Dr Matthias Landgraf, Department of Zoology, University of Cambridge (Oxidative stress and synapse growth)

Dr Keith Stubbs, Department of Chemistry, University of Western Australia (Using Drosophila models of mucopolysaccharidosis as a therapeutic screening tool)

Dr Fen-Biao Gao, Department of Neurology, University of Massachusetts, Worcester (A Drosophila model of Frontotemporal Dementia)

Dr Sarita Hebbar and Dr Dominik Schwudke, NCBS, Bangalore, India (Using Drosophila to model Lysosomal Storage Disease).

Available PhD research projects

Identifying enhancers and suppressors of Frontotemporal Dementia in a Drosophila model (2014-15)

Frontotemporal Dementia (FTD) is a major cause of early onset dementia. Characterised by atrophy of the frontal and temporal lobes with loss in language and social function, FTD incidence has a strong dominant genetic component. A number of loci have been mapped. Among these is CHMP2B encoding a subunit of ESCRTIII, a complex required for endosomal function. We have used mutant CHMP2B to perform genetic screens in Drosophila for enhancers and suppressors of an FTD related phenotype in the fly eye. We have preliminarily mapped 29 loci, three of which we have identified and characterised in detail: a regulator of the Toll innate immune pathway (Ahmad et al., 2009, PNAS), a component of phagosome maturation (Lu et al., 2013, Mol Cell) and a regulator of the endosomal recycling pathway (paper in preparation). This project will focus on fine mapping and identifying other loci from the screen. Once identified, fly genetics, cell biology and physiology will be used to define the cellular function of such proteins critical to FTD onset and progression. This project is a collaboration with Professor Fen-Biao Gao of the Department of Neurology, University of Massachusetts, Worcester. Exchanges between labs may play an important part of the project.

Dr Sean T Sweeney

Contact details

Dr Sean T Sweeney
Lecturer
Department of Biology (Area 9)
University of York
Heslington
York
YO10 5DD

Tel: 01904 328537