Unveiling The Origin Of Munc18-1 And Alpha-synuclein Co-aggregation At Nanoscale
Funder
National Health and Medical Research Council
Funding Amount
$620,005.00
Summary
Our recent work on Munc18-1 mutations leading to a severe form of human early infantile epileptic encephalopathy (EIEE) led us to uncover a critical role for Munc18-1 in controlling the formation of toxic protein aggregates containing ?-Synuclein. Targeting the Munc18-1 ?-Synuclein interaction may have therapeutic values not only for EIEE but also for other neurological diseases characterised by protein aggregations.
Cellular Effects Of Glucocerebrosidase (GBA) Mutations In Lewy Body Diseases
Funder
National Health and Medical Research Council
Funding Amount
$524,820.00
Summary
Approximately 1 in 100 people are carriers of mutations in the glucocerebrosidase (GBA) gene and are at considerably greater risk of diseases characterised clinically by parkinsonism and by the presence of Lewy body-related pathology. This study will provide tissue-based evidence of the cellular lipid and protein changes relating to Lewy body formation in patients with GBA mutations, providing the information necessary to identify the pathways and mechanisms involved.
DUAL AND MULTIPLE PROTEINOPATHIES IN NEURODEGENERATIVE DEMENTIAS – RISK FACTORS, PROGNOSTIC INDICATORS AND CLINICAL RAMIFICATIONS
Funder
National Health and Medical Research Council
Funding Amount
$604,644.00
Summary
Dementia is the umbrella term used to refer to a number of different clinical presentations,each associated with distinct histopathological signatures of protein aggregates and spread.However, converging evidence now suggests the common co-occurences of dual/multiple proteinopathies across dementia syndromes.The present study will identify the clinical ramifications and factors that are most predictive for such proteinopathies in a large cohort of longitudinally-studied patients with dementia.
VISUAL HALLUCINATIONS: MECHANISTIC BIOMARKERS AND NOVEL TREATMENTS
Funder
National Health and Medical Research Council
Funding Amount
$464,793.00
Summary
This proposal will address an urgent need to develop novel treatment strategies for hallucinations. A critical starting point in this endeavour is to look at the pathophysiology underlying hallucinations because these mechanisms represent the targets that can be modulated by treatment. This proposal will provide strong evidence for two biomarkers of hallucinations 1. Behavioural and 2. Neural.
Alpha-synuclein Metabolism In Human Neurodegenerative Disease
Funder
National Health and Medical Research Council
Funding Amount
$381,430.00
Summary
Alpha-synuclein is an abundant brain protein of unknown function. Gene mutations have been linked to rare cases with inherited Parkinson s disease. Now this protein is believed to play an important role in all forms of Parkinson s disease, Lewy body dementia, and multiple system atrophy. These diseases are designated as synucleinopathies to emphasize the potential importance of alpha-synuclein in these disease. Recent studies suggest alpha-synuclein may also contribute to many other human diseas ....Alpha-synuclein is an abundant brain protein of unknown function. Gene mutations have been linked to rare cases with inherited Parkinson s disease. Now this protein is believed to play an important role in all forms of Parkinson s disease, Lewy body dementia, and multiple system atrophy. These diseases are designated as synucleinopathies to emphasize the potential importance of alpha-synuclein in these disease. Recent studies suggest alpha-synuclein may also contribute to many other human diseases, including Alzheimer s disease. The reason how and why alpha-synuclein is involved in so many human neurological diseases is not clear. We recently discovered that alpha-synuclein in normal human brain exists in multiple form of N-terminal fragments, presumably generated through certain endogenous enzymes. These cleaved products are markedly increased in Parkinson s disease. Studies by other groups suggest alpha-synuclein and fragments may be released to the cerebrospinal fluids. Based on these findings, we hypothesize that alpha-synuclein is modified by specific enzymes in neurons and released. This is probably a normal alpha-synuclein metabolic pathway whose homeostasis may be, for reasons yet to be understood, altered in synucleinopathies. Similar mechanism may be also involved in other common diseases in which the protein is believed to play a role. This project aims to elucidate the potential role of alpha-synuclein metabolism in Parkinson s and related diseases by examining alpha-synuclein metabolites in the brains affected by these diseases. Results from this grant will provide new information about alpha-synuclein metabolism in neurons, new insights into the mechanistic involvement of alpha-synuclein in these neurodegenerative diseases. Antibody reagents generated from this study may be valuable in neuropathological and clinical assessment of changes in synucleinopathies.Read moreRead less
Alzheimer's Disease And Dementia With Lewy Bodies: How Different Are They?
Funder
National Health and Medical Research Council
Funding Amount
$565,500.00
Summary
Dementia is a devastating disorder, taking the individuals mind. As the population ages, a significant proportion become demented, impacting on these individuals, their families and the community as a whole (Federal and State budgets for this disorder are costed in the billions). There are many cellular causes of dementia, the most frequent being considered Alzheimer's disease. However, many people currently thought to have Alzheimer's disease have another dementia cause - dementia with Lewy bod ....Dementia is a devastating disorder, taking the individuals mind. As the population ages, a significant proportion become demented, impacting on these individuals, their families and the community as a whole (Federal and State budgets for this disorder are costed in the billions). There are many cellular causes of dementia, the most frequent being considered Alzheimer's disease. However, many people currently thought to have Alzheimer's disease have another dementia cause - dementia with Lewy bodies. This study aims to determine 1) how common these two types of dementias are (currently unknown) 2) how better to diagnose them and tell them apart 3) how badly the brain is affected by each disorder and 4) whether the same genes are involved in both disorders. The knowledge we will gain will allow better diagnosis of the cellular causes of dementia, knowledge necessary for rational treatment.Read moreRead less
Targeting Small Heat Shock Proteins In Diseases Associated With Alpha-synuclein Aggregation
Funder
National Health and Medical Research Council
Summary
This research will provide fundamental insight into processes that control the onset and progression of neurological diseases such as Parkinson’s disease, and may lead to the development of novel drugs to treat these disorders. The work will increase Australia's international research standing and provide high-quality multi-disciplinary training to research students.
Blood Proteins For Early Discrimination Of DEmentias
Funder
National Health and Medical Research Council
Funding Amount
$498,412.00
Summary
bPRIDE aims to develop blood biomarkers for early and specific diagnosis of the main dementia types: Alzheimer's disease, frontotemporal dementia and dementia with Lewy bodies, and use these to develop diagnostic tests.
Investigating Biometal Dyshomeostasis In Dementia With Lewy Bodies
Funder
National Health and Medical Research Council
Funding Amount
$554,644.00
Summary
Dementia with Lewy bodies (DLB) is the second most common form of dementia after Alzheimer's disease (AD). Very little is known about what causes DLB and there are currently no effective therapeutics. An imbalance in naturally occurring biological metals such as iron and copper have been implicated in AD and Parkinson’s disease so this project will investigate if metals are involved in DLB. The ultimate goal of this project is to identify if metals are a valid target for future drug development.
Lewy Bodies In Patients With Dementia – Determining Common And Unique Mechanisms In Relation To Alzheimer’s Disease
Funder
National Health and Medical Research Council
Funding Amount
$604,644.00
Summary
Alzheimer’s disease is the most common type of dementia but often has multiple mixed pathologies. For example, Alzheimer post mortem brains may have abnormal accumulation of Lewy bodies in certain parts of the brains, and could be diagnosed as Lewy body disease. This may represent a skewed representation of some dementia subtypes. This project will identify the biological determinants of dementia patients with Lewy body disease for better understanding and future therapeutic targeting.