NZ scientists' discovery holds hope for people with brain disorders
Drs Tom Brittain and Joanna Skommer of the University of Auckland’s School of Biological Sciences, working in collaboration with Dr Subadhip Raychaudhuri at the University of California, Davis, have discovered that the protein neuroglobin may protect against diseases such as Alzheimer’s by preventing brain cells (neurons) from dying in response to physiological stress. This discovery opens new avenues for future therapeutic interventions in several neurological disorders.
Neuroglobin was first identified in 2000 by German scientists Thorsten Burmester of the Institute of Zoology, University of Hamburg and Thomas Hankeln of the Institute of Molecular Genetics, Johannes Gutenberg University of Mainz. It was found to be expressed mainly in the brain (hence neuroglobin). Until then, only two proteins from this globin protein family had been described, each of them important for regulating cellular oxygen. Since its discovery, scientists have learned that neuroglobin protects cells from damage caused by lack of oxygen (as in stroke) and amyloid toxicity (the toxic accumulation of the amyloid protein in the brain seen in Alzheimer’s disease). Exactly how neuroglobin saves cells from dying a natural death has, however, remained unclear until this latest study.
Neuroglobin occurs in various regions of the brain and at particularly high levels in neurons. Scientists had previously correlated low levels of neuroglobin in brain neurons with an increased risk of Alzheimer’s disease, and recent studies have hinted that neuroglobin protects cells by maintaining the function of mitochondria and controlling the levels of important chemicals within the cell. Mitochondria are the power generators of the cell that convert oxygen and nutrients into the energy ‘currency’ that power the cell’s metabolic activities – without proper mitochondrial function, cells simply cannot survive, and die very quickly. Each cell contains between hundreds and thousands of mitochondria. Cell death associated with mitochondrial dysfunction is common in neurodegenerative diseases such as Alzheimer’s and Huntington’s, and in acute neurological events such as stroke.
In Drs Brittain and Skommer’s study, a considerable effort was put into examining how neuroglobin functions in cells experiencing stress that leads to cell destruction (essentially mimicking local conditions in the brain after stroke and in Alzheimer’s disease). Their research found that neuroglobin preserves the functioning of a cell’s mitochondria by neutralising the molecule called cytochrome c that triggers the cell’s collapse. The scientists believe that the fundamental role of neuroglobin found in brain cells is to prevent accidental cell death from occurring due to physiological stress associated with normal cell function. Cells may even protect themselves from triggering the chain of events leading to cell death by expressing a high level of neuroglobin. In Alzheimer’s disease, it is hypothesised that amyloid protein accumulates in brain neurons and leads to the rupturing of mitochondria. As this rupturing occurs, the mitochondria produce the cytochrome c which attaches to other molecules within the cell and produces the apoptosome protein. This protein causes the cell to ‘suicide’ and is known as apoptosis. This type of cell death is common following stroke and in neurodegenerative diseases. In their study, Drs Brittain and Skommer developed predictions based on intensive computational modeling of cell death carried out in Dr Raychaudhuri’s laboratory. They then validated these predictions in cell culture experiments in their University of Auckland laboratory. They discovered that neuroglobin binds to cytochrome c and neutralises it, thereby preventing it from forming an apoptosome. Ultimately, this finding suggests that high neuroglobin levels may protect neurons against the effect of this protein by preventing apoptosomes from forming.
Dr Skommer says the team is very excited by their findings, and thrilled that because of the recent funding from the Neurological Foundation, the Auckland research team can continue to work with the University of California to progress this study. “Neuroglobin holds a great deal of potential for affecting the survival of nerve cells, and we are discovering some of the exciting molecular mechanisms underpinning this fundamental role, but there is still much, much more research work to do. The research we are working on now is designed to further develop our understanding of the relationship between neuroglobin and cytochrome c so we can determine potential methods for enhancing cell survival.” The research team will report on this latest study in 2011.
The scientists say that their discovery could lead to a treatment of a number of neurological conditions involving physiological cell death, including stroke and Alzheimer’s disease, but emphasise that the development of a drug to treat the neurological diseases associated with cell death will be an extensive and lengthy process.
The team, including Associate Professor Nigel Birch and PhD student Kristen Henty at the University of Auckland, published the results of their study in Apoptosis, an international, peer-reviewed journal that is devoted to the rapid publication of innovative, basic and clinically oriented investigations into programmed cell death.