Targeting microglia in neurodegenerative diseases

Research Opportunity
PhD students, Honours students
Number of Honour Places Available
2
Department
Medicine and Radiology
Location
St Vincent's Institute of Medical Research
Primary Supervisor Email Number Webpage
Professor Michael Parker mparker@svi.edu.au 03 83442211 Personal web page
Co-supervisor Email Number Webpage
Dr Jon Gooi jgooi@svi.edu.au Personal web page

Summary Microgial cells, the resident immune cells of the central nervous system, act as the first and main form of immune defense against toxic molecules involved in neurodegenerative diseases. We are using structural biology to learn how to modulate microglia receptors to eliminate these toxins from the brain.

Project Details

Dementias, such as Alzheimer's and Parkinson's diseases, are the fourth biggest killer in developed countries. A growing body of literature implicates microglial activation as a key point in the pathogenesis of a variety of neurodegenerative disorders including dementias and a potential avenue for the development of novel therapeutic agents. Microglial cells are innate immune cells of the central nervous system (CNS) and act as the first and main form of active immune defence. Upon detection of pathogens or damage, microglia adopt an activated state resulting in an inflammatory response. The activated microglia respond to alterations in brain tissue homeostasis by changing their gene expression profile, leading to the release of a host of neuroactive signalling molecules, such as neuroinflammatory cytokines, that can contribute to the pathophysiology of a wide range of neurodegenerative diseases and psychiatric disorders. Microglial cells can eliminate toxins generated in these diseases in a process called phagocytosis which involves engulfing the toxins followed by internalisation, destruction and elimination from CNS. However, in neurodegenerative diseases the microglia can be overwhelmed by the amount of toxic species present.

We have been focusing our work on microglial cell surface receptors that can be potentially modulated by small molecule ligands to increase phagocytosis whilst decreasing production of neuroinflammatory cytokines. Our pipeline for drug discovery starts by expressing and purifying target protein receptors, crystallising the proteins and determining their 3D atomic structures by X-ray crystallography at the Australian Synchrotron. We then use these structures to identify small molecules that will bind to the proteins by docking millions of molecules (virtual screening), one at a time, into cavities (druggable pockets) on the protein surface. We then purchase the most promising molecules and test whether they bind to the protein using direct binding assays. The tightest binding ligands are then tested in microglial assays to assess phagocytosis activity and cytokine production. Active molecules are then transformed into drug-like molecules using medicinal chemistry guided by the crystal structure. An example of our recent work in the area can be found in reference 1.

1. Miles LAHermans SJCrespi GAN, Gooi JHDoughty LNero TLMarkulić JEbneth AWroblowski BOehlrich DTrabanco AA Rives MRoyaux IHancock NCParker MW. Small Molecule Binding to Alzheimer Risk Factor CD33 Promotes Aβ Phagocytosis. iScience. 2019 Sep 27; 19: 110–118.



Faculty Research Themes

Neuroscience

School Research Themes

Neuroscience & Psychiatry



Research Opportunities

PhD students, Honours students
Students who are interested in joining this project will need to consider their elegibility as well as other requirements before contacting the supervisor of this research

Graduate Research application

Honours application

Key Contact

For further information about this research, please contact a supervisor.

Department

Medicine and Radiology

Research Node

St Vincent's Institute of Medical Research

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