Protein aggregation related diseases

Protein-aggregation related diseases

In a healthy cell, the production and degradation of protein are integrated with processes that ensure the proper folding of these proteins and the prevention of unfolded proteins aggregating. Misregulation of this balance can lead to diseases such as Parkinson’s Disease, Motor Neuron Disease and Alzheimer’s. Our researchers investigate the molecule mechanisms of protein aggregation and work on the next generation of therapies against these diseases.

Molecular Horizons is closely affiliated with The Proteostasis & Disease Research Centre (PDRC) which aims to actively promote collaborative projects and provide a supportive environment to cultivate Australian proteostasis research. 

Research groups

Emerging evidence suggests ancient viral sequences which make up almost 10% of our DNA, known as endogenous retroviruses, contribute to the appearance and spreading of molecular clumps throughout the brain. This ‘clumping’, or aggregation, is a central signature of many neurodegenerative disorders including Alzheimer’s and Motor Neuron (MND) diseases. Our mission is to understand the Neurobiology of Endogenous RetroViruses in both health and disease: we are the NERVLAB! Our team is developing a unique molecular toolbox spanning orders of magnitude, from single molecules to whole proteomes, which allows us to quantify and characterise ERVs in complex biological samples in unprecedented detail.

We are using this cutting-edge toolbox, combining super-resolution microscopy and proteomic techniques, to identify specific ERV signatures in patient-derived biofluids, to benchmark experimental models, and to explore the interplay between genetic diversity, aggregation and ERV expression in the context of neurodegeneration. Our ultimate goal is to translate these fundamental insights into novel diagnostic and therapeutic strategies with the potential to have tangible impact on the lives of those living with MND worldwide.

View Dr Dezerae Cox's Scholars page

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The Ecroyd research focus is in the field of protein homeostasis (proteostasis), an important area of research as disturbances in proteostasis can lead to protein aggregation (i.e. the clumping of proteins into large deposits), a pathological hallmark of many human diseases, including Alzheimer’s disease, Parkinson’s disease and Motor Neurone Disease (MND). Research in the Ecroyd lab focuses on the role of molecular chaperone proteins in proteostasis. This is because these are the body’s front-line defenders against protein aggregation. By identifying innovative approaches to activate molecular chaperones, the group aims to develop new drugs to treat, and ultimately prevent, neurodegenerative diseases such as MND.

Work currently being undertaken in this laboratory extends from molecular biology-based techniques to recombinant protein expression and purification, in vitro biochemical assays of chaperone protein activity, to mammalian cell culture and the study of protein expression and modification in animal tissues. Of late, my group has been involved in developing novel techniques to study heat-shock chaperone function in cells and a flow cytometry-based method to count and physically isolate protein inclusions from cells. The group are also developing new single-molecule approaches so that, for the first time, we can see and characterise the interactions between heat-shock proteins and aggregation-prone proteins.

The small heat shock protein Hsp27 (HSPB1) bound to the surface of an a-synuclein amyloid fibril. This image was obtained using Total Internal Reflection Fluoresence (TIRF) microscopy. We think, by binding to amyloid fibrils, these molecular chaperones protect the cell from their toxic effects.

View Professor Heath Ecroyd's Scholars page

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The Vine‐Perrow Lab is a dynamic and innovative research group dedicated to advancing the understanding and treatment of motor neuron disease (MND). Our research efforts are driven by an urgent need to address the challenges faced in the development of effective treatments for MND. Over the past two decades, the majority of clinical trials for MND have yielded disappointing results, primarily due to significant barriers in therapeutic agent bioavailability, inefficient delivery to the central nervous system (CNS), and complexities in therapeutic administration. My lab draws from longstanding experience in developing targeted therapies for cancer to overcome the challenges posed by the blood‐brain barrier (BBB) and blood‐spinal cord barrier (BSCB) to enable effective delivery of systemically administered agents to the CNS. Specifically, we focus on the delivery of antisense oligonucleotides to the CNS using calcium phosphate lipid nanoparticles in combination with focused ultrasound, a non‐invasive method to transiently and safety open the BBB and improve drug delivery to the CNS. Our team employs a multidisciplinary approach, combining expertise in cell and molecular biology, nanotechnology and focused ultrasound to develop innovative solutions for the treatment of MND.

The Wilson research group is focussed on both basic and applied science relating to chaperones and protein folding, with a special emphasis on a novel group of (normally secreted) extracellular chaperones discovered by us. We reported the first known extracellular chaperone in mammals (clusterin) and have continued to discover new examples of this small but growing family of important molecules. Our studies include in vitro structure-function studies of extracellular chaperones, and also encompass work in small animal models (Drosophila, zebrafish and C. elegans) addressing basic science questions and specific disease scenarios. We have also developed new fluorescence-based technology platforms, including a high-throughput flow cytometry system currently being applied in a search for novel drugs to treat motor neurone disease.

A 3-colour image of a stressed cell: nucleus (blue), endoplasmic reticulum (red) and a chaperone (BiP; green)

View Senior Professor Mark Wilson's Scholars page

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The Yerbury lab is dedicated to understanding the molecular mechanisms underpinning Motor Neurone Disease (MND), with a particular focus on protein misfolding and protein aggregation. Utilising a broad array of methods ranging from the fields of biophysics, biochemistry, and cell and molecular biology, we study the basic biological processes that lead to protein aggregation, with the aim of identifying and developing novel therapeutic strategies for the treatment of MND.

Currently, we are developing a powerful high-throughput microscopy method to screen novel and clinically-approved compounds for their protective properties against MND-related protein aggregation in cultured cells. Utilising this approach, we are able to identify clinically-translatable compounds and assess their therapeutic potential in preclinical models, in an effort to uncover novel treatment avenues for MND.

Motor neurons in culture captured using confocal microscopy (Christen Chisholm, PhD candidate)

View Professor Justin Yerbury's Scholars page

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