Dr Woodruff is a Professor of Pharmacology who leads a research team aiming to find new therapeutic treatments for neurodegenerative disorders. Current therapies for these diseases are vastly inadequate, and so new research is needed to identify novel targets to slow or halt their progression. Prof Woodruff’s specific research revolves around the innate immune system in the brain, and the role of neuroinflammation in propagating disease. A key focus of his current work is testing new drugs developed at the University of Queensland in models of motor neuron disease (amyotrophic lateral sclerosis), Huntington’s disease, and Parkinson’s disease, as well as maintaining an active interest in acute inflammatory disorders including sepsis and ischemia-reperfusion injuries. Using a series of potent and orally active complement C5a and NLRP3 inflammasome inhibitors developed at UQ, Prof Woodruff’s team has demonstrated the therapeutic potential of targeting innate immune-mediated neuroinflammation to reduce neuronal cell death in animal models of these neurodegenerative diseases. His team has recently shown that in addition to their roles in neurodegeneration, innate immune factors also play essential roles in stem and neuronal cell development during embryogenesis, revealing the widespread physiological and pathological roles of this evolutionarily ancient immune system.
Parkinson’s disease (PD) is the second most common neurodegenerative disease. It is defined neuropathologically by nerve cell loss in the substantia nigra and the presence of protein aggregates termed Lewy bodies, of which the major component is a-synuclein. Innate immune-mediated neuroinflammation driven through microglia is a known contributor to PD pathology, however the role of the innate complement system in this process has not been investigated. Our results have demonstrated that complement activation and C5a-C5aR1 engagement is an essential contributor to a-synuclein pathology and microglial activation in PD. Fibrillar α-synuclein activated complement and generated C5a in human plasma, and C5aR1 was highly expressed on microglia in postmortem PD brains. In three distinct experimental models of PD, we found that C5aR1 is upregulated following dopaminergic degeneration in the nigrostriatal system. To test the therapeutic potential of this pathway in a chronic experimental model, we examined the efficacy of the orally active and selective C5aR1 inhibitor, PMX205, in reducing neuropathology and motor dysfunction in a 12-month α-synuclein fibril model of PD. In parallel, we utilised F18-DPA-714 PET/CT-imaging to visualise microglial activation in living mice. We identified that both prophylactic (0-12 month) and therapeutic (4-12 month) oral administration of PMX205 could ameliorate motor deficits, dopaminergic neurodegeneration, and F18-DPA-714 signals. Targeting complement C5aR1 with drugs such as PMX205 could therefore be an ideal therapeutic strategy to reduce microglial innate-immune mediated neuroinflammation, and thus slow disease progression in PD and other neurodegenerative disorders.