Targeting microglia in neurodegenerative diseases
- Research Opportunity
- PhD students
- Department / Centre
- St Vincent's Institute of Medical Research
|Professor Michael Parkerfirstname.lastname@example.org||03 83442211||Personal web page|
|Dr Jon Gooiemail@example.com||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.
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 LA, Hermans SJ, Crespi GAN, Gooi JH, Doughty L, Nero TL, Markulić J, Ebneth A, Wroblowski B, Oehlrich D, Trabanco AA, Rives M, Royaux I, Hancock NC, Parker MW. Small Molecule Binding to Alzheimer Risk Factor CD33 Promotes Aβ Phagocytosis. iScience. 2019 Sep 27; 19: 110–118.
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Department / Centre
Research NodeSt Vincent's Institute of Medical Research
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