Multiple sclerosis (MS) is the most common neurological disease of young adults, with very high costs in loss of quality of life, reduced contribution of sufferers to the workplace, and in treatment. No cures exist and its cause is unknown. It is, however, known to be a largely genetic disease - but the genes associated with it have yet to be identified. An international consortium, known as GAMES (Genes Associated with Multiple Sclerosis) has now completed a screen of all human chromosomes usin ....Multiple sclerosis (MS) is the most common neurological disease of young adults, with very high costs in loss of quality of life, reduced contribution of sufferers to the workplace, and in treatment. No cures exist and its cause is unknown. It is, however, known to be a largely genetic disease - but the genes associated with it have yet to be identified. An international consortium, known as GAMES (Genes Associated with Multiple Sclerosis) has now completed a screen of all human chromosomes using 6000 markers to identify regions with genetic differences in multiple sclerosis patients. The Australian contribution to this study was funded by the NHMRC. This project is a continuation of the first, only moving on to fine-scale mapping of the regions identified in GAMES1, so that single genes, rather than genetic regions, are the focus for the study. It also aims to ensure Australian participation as an equal player in phase II of this major international collaboration. The Australian results will contribute to the overall study. If associations identified in single countries are found in other countries, this confirms the validity of the association. In addition, genes which are only slightly associated with disease in individual countries, may become more meaningful if they are found to be associated in the studies from other countries. In this way a sensitive and robust comparison of the genes which affect predisposition to MS will be identified and this information can be used to target molecular pathways for drug intervention.Read moreRead less
A Role For Epigenetic Modifiers In Maintaining Chromosome Integrity During Passage Through The Male Gamete In The Mouse.
Funder
National Health and Medical Research Council
Funding Amount
$390,541.00
Summary
There is a high level of infertility in the human population, the majority of which remains unexplained. 15% of married couples in the United States are affected by infertility and it is estimated that the male partner is responsible for half of this. Some of this infertility is familial indicating an underlying genetic cause. An increased understanding of the underlying genes involved, should lead to improvements in treatment. The mouse, with its ability to produce large numbers of offspring an ....There is a high level of infertility in the human population, the majority of which remains unexplained. 15% of married couples in the United States are affected by infertility and it is estimated that the male partner is responsible for half of this. Some of this infertility is familial indicating an underlying genetic cause. An increased understanding of the underlying genes involved, should lead to improvements in treatment. The mouse, with its ability to produce large numbers of offspring and its ability to be genetically modified, provides an excellent model system for studying the genetic contribution to reproductive fitness. The studies outlined in this application aim to determine whether a group of genes, previously identified as a result of their effects on epigenetic gene silencing, are also involved in reproductive fitness in the mouse. Our hypothesis is that these genes encode proteins required for normal pairing and segregation of chromosomes during male gametogenesis. While none of the experiments described here involve studies on humans, the genes identified are likely to have human homologues. It will, then, be relatively simple to discover whether infertile men carry mutations in these genes. Assisted reproductive technologies (ART) now accounts for between 1% and 3% of annual births in many western countries and IVF services continue to grow. While these procedures provide an effective treatment for many infertile couples, they promote the transmission of any underlying genetic defects to the next generation. These genetic defects, therefore, need to be identified and understood. Recently it has been reported that the frequency of some rare diseases are, indeed, higher in ART offspring. Furthermore, if our hypothesis is correct and some of the genes involved are critical for chromosome integrity, then mutations in these genes may also increase the risk of cancer later in life.Read moreRead less
Niemann Pick Disease Type C And Intracellular Sterol Trafficking
Funder
National Health and Medical Research Council
Funding Amount
$317,741.00
Summary
Abnormal distribution of cellular cholesterol causes Nieman Pick Disease type C (NP-C), and is also strongly associated with common neurodegenerative diseases such as Alzheimer's disease. We aim to understand the molecular mechanisms by which cholesterol is sorted and transported in the cell. Our results may help develop effective therapeutic strategies against NP-C, Alzheimers' disease and other cholesterol related disorders.
Senataxin, A Novel Protein Involved In The DNA Damage Response
Funder
National Health and Medical Research Council
Funding Amount
$500,460.00
Summary
The human genome is constantly exposed to agents-chemicals that cause DNA damage. Some of these are generated during normal metabolism and are referred to as reactive oxygen species while others comprise damaging sunlight, radiation and a variety of chemical agents. These agents can lead to cancer and a range of pathologies to different tissues including deterioration of brain function. This project is designed to investigate these processes using a specific genetic disorder as a model system. T ....The human genome is constantly exposed to agents-chemicals that cause DNA damage. Some of these are generated during normal metabolism and are referred to as reactive oxygen species while others comprise damaging sunlight, radiation and a variety of chemical agents. These agents can lead to cancer and a range of pathologies to different tissues including deterioration of brain function. This project is designed to investigate these processes using a specific genetic disorder as a model system. This disorder is called ataxia with oculomotor apraxia type 2 or AOA2. This condition develops in the teenage to early twenties and as the name suggests is characterised by loss of control of gait together with difficulties of eye movement. It is due to reduced function of a particular region of the brain called the cerebellum responsible for controlling movement. We have initial data suggesting that cells from these patients are very sensitive to environmental chemicals and their capacity to carry out repair of damage to DNA is compromised. We will investigate the nature of the defect at the molecular level and establish the function of the protein defective in this syndrome. This information will be important to determining specific therapies for AOA2 patients and may also have relevance to other neurodegenerative disorders.Read moreRead less
MRNA Surveillance In Human Disease: Molecular Determinants Of Nonsense-mediated MRNA Decay
Funder
National Health and Medical Research Council
Funding Amount
$474,517.00
Summary
Inherited diseases are a common cause of human disability, illness and suffering. It has been estimated that 5-10% of the population will be affected by disorders with a genetic component. Thus studies on mechanisms of inherited diseases, especially those relating to genetic mechanisms with relevance across a wide range of individual disorders and gene mutations, are of great significance in diagnosis, molecular pathology and the eventual development of therapeutics. While there are many types o ....Inherited diseases are a common cause of human disability, illness and suffering. It has been estimated that 5-10% of the population will be affected by disorders with a genetic component. Thus studies on mechanisms of inherited diseases, especially those relating to genetic mechanisms with relevance across a wide range of individual disorders and gene mutations, are of great significance in diagnosis, molecular pathology and the eventual development of therapeutics. While there are many types of mutations, one relatively common type is called a premature termination mutation. Premature termination mutations introduce an inappropriate genetic signal that tells the cells to stop the formation of proteins before they are complete. This would result in the production of a protein that is shorter than normal, and these short proteins could be quite abnormal and drastically affect the normal function of cells. To overcome this, cells have developed elegant strategies that involve the deployment of quality control, or surveillance, mechanisms to remove the mutant gene product before it can be converted into an abnormal protein. This process is called nonsense mediated decay. Nonsense mediated decay is a complex process and some of the key components have been identified by studies on a small number of genes. However, our studies have identified several previously unknown aspects of the process that suggest that the currently held view of how nonsense mediated decay works is only the beginning of the story and further important complexity exists. The proposed research will explore the basic mechanisms of the surveillance process and determine the signals that initiate nonsense mediated decay. Since premature termination mutations cause one-third of all inherited genetic disorders, our studies will provide new insights into the surveillance mechanisms and will have wide applicability to our understanding of the basis of inherited disease.Read moreRead less
The Role Of Molecular Chaperones And Proteases In Mitochondrial Function
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Mitochondria are essential organelles providing the cell with essential molecules and being the source of oxidative energy in the cell. They are at the centre of many clinical conditions, ranging from genetic to common neurological diseases and other conditions related to ageing. We have been defining the way in which mammalian cells respond to the accumulation of unfolded proteins within the mitochondrial compartment and have found this produces what we have called the Mitochondrial Stress Resp ....Mitochondria are essential organelles providing the cell with essential molecules and being the source of oxidative energy in the cell. They are at the centre of many clinical conditions, ranging from genetic to common neurological diseases and other conditions related to ageing. We have been defining the way in which mammalian cells respond to the accumulation of unfolded proteins within the mitochondrial compartment and have found this produces what we have called the Mitochondrial Stress Response, a process that results in the selective upregulation of a suite of genes encoding mitochondrial stress proteins. This application deals with the question of the consequences to the cell of the creation of proteolytic environment. We have found that the two major proteases of the mitochondrion are upregulated and that this results in a marked increase in the rate of degradation of mitochondrial proteins. We aim to determine the specific roles of individual proteases in this process and the consequences of this proteolysis on the efflux of peptides from the mitochondria. This question has important medical implications, as one of the consequences of defects in mitochondrial function is the loss of cells from the affected tissue. We will also address the question of how mitochondrial biogenesis is regulated. We have recently found that the cytosolic molecular chaperone Hsp90 is required for protein import into mitochondria in mammalian cells. Since Hsp90 has hitherto been shown to be a key regulatory component in the steroid hormone and tyrosine kinase signalling pathways, this finding raises the possibility that protein import and thereby mitochondrial biogenesis may be regulated via the involvement of Hsp90.Read moreRead less
Parkinson's disease is a progressive, disabling, age-associated neurological disorder with no known cure. Several genes have been identified as causing Parkinson's disease, although mutations in leucine-rich repeat kinase2 (LRRK2) are by far the most common. The studies we propose will identify the cellular proteins that interact with LRRK2 to cause Parkinson's disease. These proteins may be amenable to future therapeutic manipulation.