Increasing evidence shows that the pathological hallmarks of Parkinson’s disease, Lewy bodies, and Lewy neurites, are extensively decorated with a large number of chemical modifications on aggregated forms of the presynaptic protein alpha-synuclein. The role of these modifications in regulating the formation of these pathological aggregates, their toxicity, or how they spread in the brain during disease progression remains unknown. The results obtained from this work will have significant implications and pave the way for the identification, validation, and prioritisation of novel aSyn species that could have the potential to be used as diagnostic biomarkers for PD or modifications and pathways that could be targeted for developing therapies to treat or slow the progression of PD.

Researchers at the QIMR Berghofer Medical Research Institute in Brisbane are undertaking ground-breaking research to help identify genetic factors influencing risk of developing Parkinson’s disease. This research, named the Australian Parkinson’s Genetics Study (APGS), will contribute towards the largest study of Parkinson’s genetics ever undertaken, the Global Parkinson’s Genetics Program (GP2).

This Parkinson’s research project aims to further validate peripheral monocyte in situ lysosomal GCase activity as a PD biomarker. The research team have established a flow cytometry assay for the specific measurement of lysosomal GCase activity in blood cells and shown that monocyte lysosomal GCase activity is reduced in PD patients, or at least a subset of PD patients.

This is a supplemental proposal following previous funding where the team developed and optimised a sample collection and processing protocol with flow cytometry assays at University of Sydney and University of Florida (WHOPPA). This project will assess the contribution of immune dysfunction in LRRK2 and GBA1 mutation carriers, allowing the team to stratify patients and implement future personalised therapy approaches.  

The Alfred Foundation will upgrade and refurbish the Neuroscience Clinical Trial Unit to create a dedicated clinical trials space at The Alfred Hospital in Melbourne to enhance the clinical trial capacity, facility and environment for patients with Parkinson’s disease. This funding grant will be used to develop a best practice clinical trials centre that can be modelled across other locations as we look to build a clinical trial network to support Parkinson’s trials in Australia.  

In this proposal the research team will test if pathogenic alpha-synuclein can be removed from the brain using four different classes of drugs that increase slow wave sleep. Our proof-of-concept study will employ a novel mouse model of PD that uses exosomal trafficking of alpha-synuclein to induce disease pathology. Outcomes from this proposal will identify if therapeutically targeting slow wave sleep can reduce brain pathology and rescue motor symptoms in a PD animal model.

Kim Ekroos, PhD, hypothesises that alterations in the metabolism of selective glycosphingolipids in specific brain regions contributes to early PD onset and accelerated progression rates. The team will determine whether certain glycosphingolipids stand out in specific brain regions in diseased tissues and will conduct deep learning computational approaches to better understand how these region-selective glycosphingolipid levels can be restored to a healthy state. This research may open up new strategies to accelerate drug treatments to slow and stop Parkinson’s.

Professor Sue and her team have discovered that the Nix protein restores mitophagy and mitochondrial function in people with the PINK1/PARKIN gene mutation and the team are now working on the theory that overexpressing the Nix protein using gene therapy will stop the progression of Parkinson’s.

Establish characterized and validated iPSC lines both with KCNJ15 mutation observed in PD patients and mutant-corrected control lines.Differentiate dopaminergic neurons from these cell lines to examine link between Kir4.2 channel and PD pathology, establishing Kir4.2 as a potential new drug target for PD

Both genetic mutations and exposure to environmental risk factors contribute to causing Parkinson’s disease (PD). Genetic risk for a PD patient could be due to multiple genes, different types of mutations or, simply, one genetic mutation, in one gene. Our team have developed novel computational tools that enable us to discover several new types of mutations and other genetic signals of PD in a person’s DNA. We will leverage these unique tools to investigate a new source of mutations, called repeat expansions, which we have already proved to be the genetic cause of diseases that are similar to PD.

Our project will test the effectiveness of a new treatment for Parkinson’s disease (PD), called RRx-001. We believe this drug could be beneficial in PD by blocking inflammasome activation and other mechanisms which drives persistent inflammation that is linked to PD progression.

The Global Parkinson’s Genetics Program (GP2) will genotype 200,000 volunteers around the world to further understand the genetic architecture of Parkinson’s disease. There is still much to learn about genetic risk factors and the path to further understanding requires working collaboratively and openly sharing data, processes, and results. The Australian Parkinson’s Genetics Study (APGS) hosted by QIMR Berghofer Medical research Institute aims to make a significant and impactful contribution to GP2.

Persistent activation of the immune cells that reside in the brain leads to a state of chronic inflammation that contributes to the degeneration of neurons in Parkinson’s disease (PD). The research team have identified a novel inflammatory target in the brain and designed a novel and selective inhibitor that enters the brain to reduce neuroinflammation and neurodegeneration.

The two objectives of this study include screening PD associated and GBA SNPs in the KOLF2 cell line in a luciferase assay and confirming that variants modulate their respective target genes. This study has the potential to identify new targets and pathways that play a role in PD and identify modifiers of GBA expression and function that can be used for patient stratification.

Sitala is a biotech company driving translational research into new therapies that will block harmful inflammation to help people living with Parkinson’s disease.

PINK1 and Parkin (PRKN) proteins are both involved in mitochondrial quality control, and loss of function mutations causing familial forms of PD with earlier onset of symptoms compared to sporadic Parkinson’s disease. This study aims to profile PRKN and PINK1 gene and protein expression,PRKN translation, and pS65-Ub levels in vivo in a cell type-focused manner, including phenotypic characterization of the brain cells to address current key knowledge gaps of expression patterns for
PRKN and PINK1.

Associate Professor Cedric Bardy’s (Flinders University – SAHMRI) study uses live human neurons (brain cells) in a petri dish to examine the biological basis of Parkinson’s disease. The neurons are generated in the lab with non-invasive stem cell technologies. The idea is to prevent overload of electrical activity occurring in patient’s neurons to rescue energy levels, protect further neuronal losses and halt the progression of the disease.

This study aims to validate the efficacy of our anti-inflammatory preclinical candidate drug in preclinical models of PD.

Gut dysfunction and microbiome dysbiosis have been linked to the onset and progression of PD pathology. However, the mechanisms by which an altered gut microbial population can initiate or contribute to disease progression remains poorly defined. We recently uncovered that the microbial pathways for synthesis of Trimethylamine (TMA) are specifically elevated in PD patients.

In Parkinson’s disease (PD) immune cells in the brain, gut and blood become persistently activated due the accumulation of synuclein aggregates and other mechanisms, which can trigger inflammation. Ongoing inflammation is accompanied by changes in the gut microbiome of people with PD. Both these processes have been shown to contribute to the gradual death of dopamine-producing cells in the brain. Therefore, halting the cycle of inflammation, microbiome dysfunction and brain cell death is considered a promising means by which to slow or stop disease progression. Our study will test a new approach by which to accomplish this.

This study will determine whether administration of CK1 inhibitors in a carefully timed manner can restore healthy sleep parameters, sleep quality and the smooth functioning of the circadian clock. We will also assess whether improvements in sleep quality and circadian rhythm lead to a reduction in other physiological changes characteristic of PD, such as brain inflammation, alpha-synuclein accumulation and the death of dopamine-producing neurons.

Antisense oligonucleotides (ASOs) offer a new therapeutic strategy in Parkinson’s disease (PD) because they can be readily targeted to genes causally linked to PD development or progression. Consequently, they may treat the underlying pathology of PD, not just symptoms, and hence profoundly alter its relentless progression and impact on patients.

Glycosphingolipids are natural cellular fats. They are components of cellular membranes that fulfill multiple functional roles, from cell structure and transport to signaling. The contribution of glycosphingolipids to Parkinson’s disease is not fully understood.

Our research interest is understanding the mechanistic and metabolic details of Glycosphingolipids, and their role within brain regions affected by Parkinson’s.

Inflammasomes are large multiprotein complexes that play a central role in the innate immune system, the body’s first line of defense against microbes. Our prior studies have shown that a key protein in the inflammasome, called ASC, is increased in Parkinson’s disease patients, and in experimental models. We hypothesize that specifically inhibiting ASC will slow the progression of disease in pre-clinical models of Parkinson’s disease.

Light, as the primary driver of circadian function and sleep, is transmitted by melanopsin expressing photoreceptors in the eye to the central body clock in the brain to regulate release of the dark hormone (melatonin) and modulate sleep and wakefulness.

Our aim is to demonstrate the positive effect of melanopsin-directed lighting on non-motor (sleep and circadian) and motor (gait, balance, tremor) symptoms.

The team has developed a method for single-molecule detection of protein aggregates to enable identification and fingerprinting of aSyn oligomeric species.

Pathogenic alpha-synuclein (aSyn) aggregates have been recently been detected in spinal fluid of people with Parkinson’s disease where its concentration shows potential to be a biomarker or indicator of Parkinson’s.

The goal of this study is to determine the effect of LRRK2 and GBA mutations on activities of both enzymes under basal/stimulated (pathogens) conditions

Repetitive DNA elements such as “jumping genes” were previously considered ‘junk DNA’. However, it is now known that these elements are involved in the development of several diseases and can regulate how much of a gene is produced. The study of these elements is complex and requires specialist software tools for their analysis, therefore they have not been widely studied in Parkinson’s disease.

There is very little data on the role of astrocytes in Parkinson’s disease. Additionally, astrocytes are notoriously regionally heterogeneous, so analysis of astrocyte expression profiles in non-PD affected brain regions may not be relevant. Dr. Halliday proposes to use digital-spatial profiling of human brain tissue from PD-relevant regions to asses astrocyte response to alpha-synuclein and expression of A1 and/or A2 like profiles.

The goal of this study is to determine if differences in mitochondrial function in lymphoblastoid cells and/or PBMCs can reliably detect prodromal status in those with a high risk of conversion to PD. Previous studies had demonstrated a clear mitochondrial deficit after discriminate analyses when multiple different readouts were combined for analysis in PD subjects vs to controls. These parameters also did not change with time. The reviewer (Sam Hasson, Amgen) suggested additional experiments to determine if these readouts could serve as biomarkers in a PD prodromal cohort.

Defects in the protein parkin cause the loss of nerve cells in the brain and are responsible for many cases of young-onset Parkinson’s disease that develops before 50 years of age. We now understand how Parkin normally needs to change its shape to function, and how this fails to occur in patients with defects in this protein. We aim to generate chemicals that provoke defective parkin to change shape and re-activate it and to establish new drugs to treat young-onset Parkinson’s disease.

Mounting evidence suggests Parkinson’s disease patients have accumulating disruption of sleep and circadian (24-hourly) rhythms which are thought to worsen other symptoms associated with PD. We have recently discovered a new pathway called Period1 (Per1) which can regulate the sensitivity of the biological clock to light. Removal or blocking of this pathway enhance the responsiveness to light which is affected in PD.

We have recently shown that a new type of toxic protein forms in the brains of people with Parkinson’s disease.  This same protein is known to cause nerve cell death in another degenerative disorder which affects movement. We therefore suggest this abnormal protein may underlie the death of brain cells in Parkinson’s disease.        

This project will leverage digital spatial profiling technology to examine multiple molecular targets on immune-oncology pathways at different pathological progression stages of PD (Braak stages) using patient post-mortem tissue. If successful, this effort has the potential of identifying novel molecular targets for early diagnosis and treatments, as well as establishing a timeline of immunopathological correlation with PD.

A clinical trial looking at constipation and gut dysfunction is now underway at the University of Queensland. The trial will determine if a targeted treatment can restore specific beneficial gut bacteria that are known to be substantially reduced in people with Parkinson’s. The latest scientific thinking suggests a strong link between gut bacteria and Parkinson’s – particularly around the harmful role that altered gut bacteria and their metabolic products may play in contributing to the disease process”

Shake It Up Australia together with our partners at The Michael J. Fox Foundation have committed funding to Professor Andrew Hill at La Trobe University to test the power of extracellular vesicles (EVs), or cell particles, to detect the disease via a simple blood test.

Our previous studies confirmed the activation of an immune system complex called the inflammasome is involved in chronic inflammation and the death of brain cells in Parkinson’s disease. Under the previous grant, we also identified and confirmed a new signaling pathway involving toxic forms of the protein alpha-synuclein that activates the inflammasome. We demonstrated that this pathway is activated in people with Parkinson’s and pre-clinical models of the disease. Crucially, blocking this pathway using a repurposed drug was beneficial in pre-clinical models.

StandingTall-PD is the first scalable self-managed solution to address excessive step-time variability, balance impairments and FOG in people with PD delivered using mobile technology (tablet, smart-phone, smart-socks and ear-buds).

With previous funding from MJFF & SIU, we determined how the activity of LRRK2 genetic mutations contributed to inflammation in Parkinson’s. We found that inflammation was higher when LRRK2 was more active. This may help explain how LRRK2 contributes to the risk of Parkinson’s disease.

A dysfunction of the glucocerebrosidase (GCase) protein increases the risk of Parkinson’s disease (PD). Blood cells called monocytes produce large amounts of this protein. The aim of this study is to determine how well the GCase protein functions in monocytes from the blood of people diagnosed with PD.

I) Assess the presence of aggregated alpha-synuclein in inclusions and as diffuse oligomers in PD (Braak stage 4 and 6) and MSA (MSA-p and MSA-C) post-mortem tissues by IHC and IF using multiple antibodies selected for alpha-synuclien including MJF-14
2) Assess the presence of aggregated alpha-synuclein in inclusions and as diffuse oligomers in PD and MSA post-mo1iem tissues by MJF-14 proximity ligation assay and fF analyses
3) Assess the correlation between the cytopathology of oligodendrocytes, astrocytes and neurons 4) Assess specific protein changes associated with inclusion formation, myelination and mitochondria

Objective measurement in Parkinson’s Disease (PD), offers significant advantages for clinical management and the clinical validation of new therapies.

The Parkinson’s/Personal KinetiGraph™ (PKG™) System provides a continuous, objective measurement of movement disorder symptoms in everyday environments, including bradykinesia (BK), dyskinesia (DK) and tremor. The PKG™ system consists of a wearable data logger, proprietary algorithms for data analyses and intuitive data presentation for clinicians (the PKG™ report).

The accumulation of aggregated alpha-synuclein in the brain is the pathological hallmark of Parkinson’s disease and is a frequent target for drugs being developed to treat PD. The ability to visualize alpha-syncuclein in the brain could be useful both as a biomarker of the presence of disease and disease progression and as a tool for drug development. The ultimate goal of this project is to develop a PET radiotracer to image the distribution of alpha-synuclein in the brain. Lead compounds that bind to alpha-synuclein will be optimized to modify certain features in order to improve selectivity and binding potency. Optimized compounds will be radiolabeled and tested in PD models. The deliverable for this funding period is one or more optimized compounds that show promise for use as a PET tracer and that will be ready for human testing in the near future.

In the brains of people with Parkinson’s disease, the GBA protein appears to no longer fully function. Thus, therapies aimed at stabilizing glucocerebrosidase (GBA) protein and/or activity are potential new treatments for Parkinson’s disease. This project will use flow cytometry to develop and test a clinically relevant biomarker assay for the simultaneous detection of GBA protein and activity in peripheral immune cells from patients with Parkinson’s disease. Altered peripheral GBA protein or activity in patients with Parkinson’s disease may constitute a convenient biomarker for selection into therapeutic trials and/or a convenient peripheral measure of the efficacy of drugs aimed at stabilizing GBA.

People with certain genetic differences (mutations) in the LRRK2 gene are at much greater risk of getting Parkinson’s. While only a small percentage of all Parkinson’s cases are directly due to LRRK2 mutations understanding what LRRK2 does and what it may do differently in Parkinson’s disease patients is a big research priority, as pharmaceutical companies are developing drugs that can block LRRK2 function. Understanding how LRRK2 mutations cause Parkinson’s disease is complicated though, as the mutations have a number of effects on the LRRK2 protein. This project aims to use new models to separate the effects of LRRK2 mutations and study them in isolation. This may help delineate how LRRK2 mutations are causing Parkinson’s disease and the best ways to therapeutically target the LRRK2 protein for new Parkinson’s disease treatments.