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Our work is perhaps best illustrated by our investigations into parkinsonism. We combine approaches from families and case-control studies in patients with parkinsonism to identify genetic factors underlying these disorders. We use tissue from the brain bank to further understand the molecular pathology. The role of oxidative stress and mitochondrial function is being evaluated and we use cell culture models to illuminate and evaluate novel disease processes. All of these investigations are driven by the clinical necessity to understand and develop more rational therapies for these incurable diseases.
There is frequently much to be learnt from comparing disease processes and we have been able to continue the work into other neurodegenerative conditions. For example, work by Prof Tamas Revesz and Dr Janice Holton into the novel familial British and Danish dementias is providing important molecular clues to the pathological and biochemical role of amyloid. Our previous studies revealed a close topographic correlation between deposition of the novel amyloid proteins ABri and ADan and neurofibrillary degeneration in these dementias. Both diseases are caused by different mutations of the BRI gene and clinically present with spasticity and dementia. In Alzheimer's disease it has been suggested that inflammation, including activation of the complement pathways, are associated with amyloid deposition and may be an important factor contributing to neurodegeneration. Our recent studies have demonstrated that the complement components colocalise with both vascular and parenchymal ABri and ADan deposits in familial British dementia (FBD) and familial Danish dementia (FDD), respectively. A number of proteins are known to be associated with Aβ protein in Alzheimer's disease and have been shown to facilitate amyloid fibril formation. Our investigations have indicated that such proteins, as in Alzheimer's disease, are also present in both ABri and ADan lesions suggesting a similar mechanism of protein aggregation with fibril formation in FBD and FDD to Alzheimer's disease. However, the differences in the degree of deposition of these components between FBD and FDD, which we also demonstrated, are the subject of further investigations. The origin of ABri and ADan deposited in the brain is not known. Our previous investigations showed that ABri is present in the circulation and is also deposited in peripheral organs. These findings suggested that the periphery may be a source of ABri deposited in the brain. Our recent studies, however, have demonstrated that both the mRNA and the ABri precursor protein, are expressed at high levels in cerebral nerve cells and also that furin, which is the enzyme implicated in the cleavage of the precursor protein, is also produced extensively in the same cells. Our finding that the precursor protein is absent from cerebral blood vessels has important implications for our understanding of the pathogenesis of cerebral amyloid angiopathy in general as this confirms that an amyloid protein may be produced at some distance from the site of the final deposition. In order to complement and enhance research activities in the genetic and pathological fields it is clearly important to attempt to elucidate mechanisms at a protein/biochemical level. The group remains focussed on neuronal-astrocyte interaction in the maintenance of mitochondrial function as related to neurodegenerative diseases. We are a key component of the pan UCL MRC Cooperative Group on Mitochondria in Health and Disease. Work continues on documenting the role of oxidative stress in the pathogenesis of neurodegeneration and how the antioxidant molecule glutathione is transported between neurones and astrocytes. Further insights into the nature of a factor, released by astrocytes, that protects extracellular glutathione have been made. Potential mechanisms whereby the mitochondrial electron transport chain may become compromised in neurodegenerative disorders associated with brain oxidative stress have been identified. Of particular interest to us is ubiquinone, the availability of which may be diminished following increased cellular exposure to nitric oxide and other reactive oxidising species.
Dr Simon Heales and colleagues continue to investigate the effect of compromised tetrahydrobiopterin availability upon cellular nitric oxide (NO) metabolism and evaluate the relationship to the biochemical changes associated with conditions such as DOPA responsive dystonia (DRD). This complements the interests of the NHNN's neurodiagnostic DNA laboratory who are developing genetic analysis of the major gene causing DRD.
Our investigations into the role of the amyloid β (Aβ) protein, characteristic of Alzheimerís pathology, and its interaction with NO, on neuronal/astrocytic function have continued. Using rat primary cell cultures we have studied the effects on the calcium dynamics and mitochondrial membrane potential (in collaboration with Professor Mike Duchen, Physiology Department, UCL). Our results indicate that treatment with Aβ induces within a few minutes dramatic calcium oscillations in astrocytes, but not in neurones. Paradoxically, when assessed 24 hours later, only the neurones will have suffered cell death, highlighting the importance of intracellular signalling between these two cell types.
The role of mitochondria in neuronal apoptosis continues to be studied and the contribution of haem oxygenase to the process of oxidative stress in neurdegeneration explored. Astrocyte/neuronal interactions in an in vitro model of hypoxia/ischaemia are being investigated are being investigated, particularly the protective role that astrocytes may play in maintaining neuronal antioxidant defences e.g. glutathione.
We are also studying the ability of a class of compounds, the manganese-salens to detoxify reactive oxygen and nitrogen species and together with Dr David Gems (Genetics, Evolution and Environmrnt, UCL) are developing a model of oxidative stress in aging using the nematode C. elegans.
We have demonstrated in septic patients a strong association between NO overproduction, antioxidant depletion, mitochondrial dysfunction and decreased ATP levels that relate to both organ failure and eventual clinical outcome. These data implicate bioenergetic failure as an important pathophysiological mechanism underlying multi-organ dysfunction. As a result of control studies we have discovered, in collaboration with colleagues at Essex University, using Electron Paramagnetic Resonance, a novel iron complex, the concentration of which correlates with reduced activity of the mitochondrial enzyme, cytochrome oxidase (complex IV) in patients with arthritis. We postulate that the loss of complex IV activity could lead to further increased oxygen radical formation and thus contribute to the degenerative nature of the disease.
