ORCID Profile
0000-0003-0308-2761
Current Organisation
University of Queensland
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Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.NBD.2019.03.003
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease without effective treatment. Although the precise mechanisms leading to ALS are yet to be determined, there is now increasing evidence implicating components of the innate immune complement system in the onset and progression of its motor phenotypes. This review will survey the clinical and experimental evidence for the role of the complement system in driving neuroinflammation and contributing to ALS disease progression. Specifically, it will explore findings regarding the different complement activation pathways involved in ALS, with a focus on the terminal pathway. It will also examine potential future research directions for complement in ALS, highlighting the targeting of specific molecular components of the system.
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.PNEUROBIO.2022.102282
Abstract: Once widely considered an immune-privileged organ, the brain is now known to be intimately intertwined with immune-system activation. In particular, the complement system, an enzymatic cascade conferring innate immunity, has crucial functions for several neurodevelopmental and neuromigratory mechanisms. Recent advances have demonstrated the neurological importance of complement activation in the adult brain, whereby phagocytosis of weakened synapses biologically encodes "forgetting" of information through complement activation. Neurophysiologically, complement factors can also influence the brain's computational processes, increasing neuronal calcium influx and neurotransmitter release and altering synaptic strength. The complement system's effects on synaptic connectivity can also be observed in many pathological conditions including epilepsy, schizophrenia, and viral-induced cognitive deficits, where perturbations of complement-stimulated synaptic remodelling lead to severe dysfunction. In this review we provide an overview of current knowledge for complement in neurodevelopment, and examine recent evidence highlighting a critical physiological role of complement in the plasticity of the adult brain. This is especially relevant due to the explosion of complement-targeted therapeutics in clinical trials to treat neurological disorders.
Publisher: Springer Science and Business Media LLC
Date: 11-2022
DOI: 10.1038/S41380-022-01831-0
Abstract: Coronavirus disease-2019 (COVID-19) is primarily a respiratory disease, however, an increasing number of reports indicate that SARS-CoV-2 infection can also cause severe neurological manifestations, including precipitating cases of probable Parkinson’s disease. As microglial NLRP3 inflammasome activation is a major driver of neurodegeneration, here we interrogated whether SARS-CoV-2 can promote microglial NLRP3 inflammasome activation. Using SARS-CoV-2 infection of transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) as a COVID-19 pre-clinical model, we established the presence of virus in the brain together with microglial activation and NLRP3 inflammasome upregulation in comparison to uninfected mice. Next, utilising a model of human monocyte-derived microglia, we identified that SARS-CoV-2 isolates can bind and enter human microglia in the absence of viral replication. This interaction of virus and microglia directly induced robust inflammasome activation, even in the absence of another priming signal. Mechanistically, we demonstrated that purified SARS-CoV-2 spike glycoprotein activated the NLRP3 inflammasome in LPS-primed microglia, in a ACE2-dependent manner. Spike protein also could prime the inflammasome in microglia through NF-κB signalling, allowing for activation through either ATP, nigericin or α-synuclein. Notably, SARS-CoV-2 and spike protein-mediated microglial inflammasome activation was significantly enhanced in the presence of α-synuclein fibrils and was entirely ablated by NLRP3-inhibition. Finally, we demonstrate SARS-CoV-2 infected hACE2 mice treated orally post-infection with the NLRP3 inhibitory drug MCC950, have significantly reduced microglial inflammasome activation, and increased survival in comparison with untreated SARS-CoV-2 infected mice. These results support a possible mechanism of microglial innate immune activation by SARS-CoV-2, which could explain the increased vulnerability to developing neurological symptoms akin to Parkinson’s disease in COVID-19 infected in iduals, and a potential therapeutic avenue for intervention.
No related grants have been discovered for Sandra Parker.