Altered Nuclear Trafficking And Nuclear Body Dynamics As Drivers Of Ataxin-1 Toxicity
Funder
National Health and Medical Research Council
Funding Amount
$755,190.00
Summary
Ataxias are a large group of neurodegenerative disorders in which balance, motor skills and memory are progressively lost. While mutations in specific proteins do cause certain hereditary ataxias, the mechanisms of their detrimental actions is unclear. Our studies probe the toxic mechanisms of the ataxin-1 protein, focusing on its partners and stress-initiated formation of a toxic hydrogel state. The outcomes will define impacts on cellular protein movement in neurodegeneration more broadly.
Structural domains of beta-tubulin and their role in microtubule dynamics and transport. This study aims to obtain a fundamental understanding of how the structural domains of the cytoskeletal protein beta-tubulin are involved in microtubule structures during cell division and vesicular transport. Using gene-editing technology and coupling this with cell biological approaches and high-resolution cell imaging will enable detailed analysis of the role of beta-tubulin domains in these important cel ....Structural domains of beta-tubulin and their role in microtubule dynamics and transport. This study aims to obtain a fundamental understanding of how the structural domains of the cytoskeletal protein beta-tubulin are involved in microtubule structures during cell division and vesicular transport. Using gene-editing technology and coupling this with cell biological approaches and high-resolution cell imaging will enable detailed analysis of the role of beta-tubulin domains in these important cellular processes. The outcomes will include fundamental new knowledge in cell biology and lead to the development of unique biological models that can be used to understand disease.Read moreRead less
Nuclear architecture is critical to the preservation of genome integrity. The aim of this research proposal is to delineate the role of chromatin organisation in transcription factor target search and damage site recruitment of DNA repair factor machinery. To achieve this I have developed fluorescence microscopy methods to monitor changes in chromatin structure with submicron resolution. Only with this technology can I determine how chromatin dynamics maintain genome integrity or induce disease.
Unraveling The Dynamic Munc18a:Syntaxin1 Interaction Required For Neurotransmission
Funder
National Health and Medical Research Council
Funding Amount
$674,591.00
Summary
Membrane trafficking, the topic of the 2013 Nobel prize in Medicine, is required for delivery of cellular cargo. This research will investigate the interactions and structures of proteins from the neuronal membrane trafficking system. Understanding how this system operates will expand our knowledge of processes fundamental to learning and memory and may ultimately lead to development of selective therapeutics for treating a range of diseases.
The Role Of Intracellular Protein Trafficking In Alzheimer's Disease
Funder
National Health and Medical Research Council
Summary
Alzheimer’s disease (AD) is a progressive neurological disorder and is the most common cause of dementia. The development of therapies must be preceded by a thorough understanding of the molecular processes that underpin the disease. In this project we will examine the interactions between the Alzheimer’s precursor protein (APP) and the molecular machinery that controls its intracellular localization and breakdown to the toxic A? peptide that is central to disease pathology.
The Role Of Protein Glycosylation In The Malaria Parasite
Funder
National Health and Medical Research Council
Funding Amount
$644,428.00
Summary
The parasites that cause malaria have unique proteins on their surface that are essential for infection of humans. These proteins are useful for making vaccines to train our immune system to recognize and block infection by the malaria parasite. Our latest research has shown that these proteins are modified with sugars that enhance parasite virulence. We are studying these modifications more closely to facilitate the development of improved malaria vaccines.
Endosomal Sorting Of Amyloid Precursor Protein In Alzheimer's Disease
Funder
National Health and Medical Research Council
Funding Amount
$858,643.00
Summary
Alzheimer's Disease is a progressive neurological disorder and is the most common cause of dementia. Effective treatments are desperately needed, but none are currently available. The toxic amyloid peptide A? is central to disease pathology and is derived from breakdown of the Alzheimer’s amyloid precursor protein (APP). In this project we will examine the interactions between APP and the molecular machinery that controls its location in the cell and subsequent degradation.
Enhanced Nuclear Transport In Transformed Cells; Implications For Cancer Treatment
Funder
National Health and Medical Research Council
Funding Amount
$628,650.00
Summary
We have found that cancer cells are different to normal cells in terms of their ability to accumulate molecules in the cell nucleus. We intend to pursue this observation in detail, to understand the mechanism thereof, and the extent to which all types of cancer cells are similar in this regard. The results will have high relevance to understanding of oncogenesis, and of utility in approaches to anti-cancer therapies relying on the delivery of nuclear acting drugs.
Membrane Trafficking Of BACE1 And Amyloid Precursor Protein In Primary Neurons And The Production Of Abeta Amyloid Peptides
Funder
National Health and Medical Research Council
Funding Amount
$705,984.00
Summary
The development of Alzheimer’s disease results from the generation of toxic peptides by the cleavage of a membrane protein by an enzyme called BACE. A key feature of which regulates the generation of toxic peptides involves the movement of BACE between compartments in the cell by a process known as membrane transport. Our recent work has identified the itinerary of BACE in the cell. The studies here will reveal the molecular machinery of the BACE pathway in neurons. This fundamental informati
Membrane Trafficking Of The ?-secretase, BACE1, And The Generation Of Alzheimer's Disease A? Amyloid Peptides
Funder
National Health and Medical Research Council
Funding Amount
$465,704.00
Summary
Alzheimer’s disease results from the production of toxic neuropeptides by the action of an enzyme called BACE. The generation of toxic peptides requires the movement or trafficking of BACE between different cell compartments. This research will reveal the molecular machinery of the BACE transport pathway. This new knowledge will provide a strategy to develop drugs to inhibit BACE activity and the production of the toxic peptide, which would be of significant benefit to patients and families.