Quick Project Snapshot
Effect of tau phosphorylation on exosome release in cell culture systems
The structural protein tau is implicated in a number of debilitating neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease. Following translation of the tau gene, the tau protein is subject to a number of post-translational modifications (PTMs), one of which, Tau hyperphosphorylation, is characteristic in AD brain. Our laboratory studies the functional consequences of tau modifications and their potential to underlie disease processes. Our recent findings indicate that PTMs of tau may alter the ability of the cell to traffic and remove proteins scheduled for destruction in the cell, leading to aberrant release of these proteins in encapsulated, extracellular vesicles termed exosomes. Exosomes are a recently discovered, alternative inter-cellular signalling system that may be hijacked to transmit pathological signals from cell to cell across the body. This project aims to examine the effect of tau hyperphosphorylation on the release of exosomes in cell culture systems, and to determine the potential impact of this mechanism in the propagation of pathology in the Alzheimer’s disease. Techniques employed will include cell culture, the use of pharmacological tools to manipulate tau phosphorylation, Western-blotting, and exosome extraction and characterisation using transmission electron microscopy.
This laboratory has expertise in Medicinal Chemistry (in association with Prana Biotechnology) and in biomarker discovery. More recently, it has focussed on the pathways leading to Parkinson’s disease, especially around the oxidative modifications of tau.
The Australian Imaging, Biomarker and Lifestyle (AIBL) Study, the Dementia Collaborative Research Centres (DCRC) and the Cooperative Research Centre for Mental Health (CRCMH). AIBL, DCRC and the CRCMH are intimately involved in our research programs, relying on patient cohorts for biomarker and imaging discovery in both neurodegenerative and psychotic illness.
Translation of our research findings into clinical practice will become more important over the next five years, as we move from a series of failed or equivocal phase 3 drug trials sponsored by the pharmaceutical industry. There is now general agreement that these drug trials need to be based at the earliest possible stage of Alzheimer’s disease, hence our participation in the Dominantly Inherited Alzheimer Network (DIAN) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (the A4 study). These two pre-clinical trials are designed to administer drugs in the preclinical phases of both familial and sporadic Alzheimer’s disease.
All Projects by this LabEffect of Abeta on excitotoxic signalling pathwaysEffect of tau phosphorylation on exosome release in cell culture systemsThe influence of alpha-synuclein on olfactionThe role of peroxinitrite in depressionThe role of tau protein in olfactory processesAre exosomes driving Alzheimer’s disease pathogenesis?Discovering how toxic proteins traffic from cell to cell in Alzheimer’s disease.Uncovering the role of exosome derived lipids in Alzheimer’s disease.
Dr Lachlan Thompson
Prof David Finkelstein
Scientists in the Neurodegeneration division interrogate how neurones live, die and can be rescued to improve brain function in degenerative conditions such as Parkinson’s and Motor Neuron Diseases. There is no effective treatment for Motor Neurone Disease and the incidence of Parkinson’s Disease is rising alarmingly in our aging community. Gene abnormalities, energy deprivation, toxic rubbish accumulation and inflammation all contribute to a toxic environment for brain cells. Our teams study these events in animal models and cultured cells, with a view to translating knowledge into new therapies for human patients.