Extracellular Vesicle Group

The microbiota-gut-brain axis is beginning to take centerstage in Parkinson’s disease (PD) research, as the spotlight becomes fixed on microbiotic dysbiosis as a contributor to PD pathogenesis. It is hypothesised that the gut microbiota promotes local, systemic, and neural inflammation, which can promote neurodegeneration in PD, however how bacteria influence these processes remains unclear. We propose that Outer membrane vesicles (OMVs) released from gram-negative bacteria are a mediator of PD, due to their immune stimulatory composition, including containing potent lipopolysaccharides (LPS) and capability to impact gastrointestinal permeability and influence global inflammation.

Methodology: OMVs are isolated from bacterial culture or murine faeces and characterised by density, size, morphology, LPS content and ability to stimulate immune cells in vitro. OMVs from bacterial culture or an equivalent dose of LPS are orally administered to a PD model mouse to determine if OMVs contribute to the acceleration and exacerbation of PD inflammation, and gastrointestinal and neurological dysfunction.

Lipid dyshomeostasis is associated with various disorders including Alzheimer’s disease (AD). The work from our laboratory (Su et al, JEV 2021), and others, suggests that extracellular vesicles (EVs) contain lipid biomarkers that could aid in the diagnosis of AD and diseases associated with impaired lipid metabolism.

Knowing the lipid content of EVs is a key first step to discovering EV-based lipid biomarkers in blood. Some studies have reported the lipid content of ‘’EVs’’ in blood. However, used EV isolation techniques that are known to co-isolate free lipid and lipoproteins.

In this project we aim to:

• demonstrate the importance of size exclusion resin size to isolating highly enriched EVs for lipidomic analysis
• develop a reference EV plasma lipidome for the research community
• determine if plasma EVs report on lipid dyshomeostasis in Alzheimer’s disease.

Methodology: Human plasma EVs are isolated using commercially available kits or by density fractionation and size exclusion chromatography and characterised by western blot, transmission electron microscopy, and quantitative mass spectrometry based proteomic and lipidome analysis.

This project is in collaboration with Professor Gavin Reid and Associate Professor Kevin Barnham.

Here, we are using exosomes as a tool to interrogate the intracellular pathways implicated in Parkinson’s disease. We hypothesise that the composition of exosomes will provide fresh insight into the pathophysiology of the disease and thereby reveal potential disease biomarkers and therapeutic targets.

Methodology: EVs are studied in the context of cell culture models of subtle mitochondrial dysfunction and oxidative stress and in tissues from individuals with Parkinson’s disease.

Capable of delivering lipid, protein, and nucleic acids to both nearby and distal cells, EVs have been hypothesized to contribute to the progression of neurodegenerative diseases, including Huntington’s disease (HD). To date, most analyses on the role of these vesicles in the healthy and diseased state have relied on studying vesicles from in vitro sources, such as conditioned cell culture media, or body fluids. Here, we are isolating EVs direct from mouse and human Huntington’s brain tissue. Understanding the role of EVs in HD will inform pathogenic mechanisms of the disease and could lead to the identification of new therapeutic targets.