Research outline - Laboratory of Motor and Sensory Systems
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The cause of sporadic Parkinson’s disease, which accounts for 90-95% of cases, is unknown. One of the principal fields of research into Parkinson’s disease is investigation into the nature of the underlying pathologies. These are important as they may give us some clue as to what might be triggering the disease. In particular these pathologies include, increased levels of oxidative stress, loss of dopaminergic neurons, the presence of protein inclusions known as Lewy Bodies, selective deficits in complex I of the mitochondrial electron transport chain, decreased levels if the antioxidant glutathione, increased levels of iron, increased levels of apoptosis and increased levels of microglial activation.
In addition to these, another important consideration is not only what pathologies exist but where they occur. Patholigical changes have been shown to occur over a larger number of regions in the brain including, the dorsal motor nucleus of the vagus nerve, the olfactory bulb, the locus coeruleus, the lower raphae nuclei, the adjoining reticular formation, the central subnucleus of the amygdala, the tegmental pedunculopontine nucleus and magnocellular nuclei of the basal forebrain. Later, the changes spread to the substantia nigra pars compacta, the temporal cortex, the insular and cingulate cortices as well as the temporal cortex.
Lastly the disease is progressive and is observed to spread over the brain for up to 30 or more years. Taken together, then, we see that there are a large number of pathological mechanisms, occurring in a large number of brain regions over a very long space of time. It is highly unlikely that all of these pathologies occur in each of the brain regions involved at each time point, independently of one another. It is therefore likely that they are instead triggered by a single insult. We hypothesize that this insult initiates a cascade of events which then progresses independently of the initial trigger.
Since the disease has been progressing for 30 or more years in human Parkinsonian patients by the time their brain is available to study, it is difficult, if not impossible, to examine the early initiating events in the human. Instead a model of possible initiating events must be created to see if the pathologies associated with Parkinson’s disease are recreated as a result of our hypothesized trigger.
One possible initiating trigger of Parkinson’s disease we are examining at present is a reduction in the number or function of astrocytes. In order to do that we are ablating astrocytes in the substantia nigra, a principal site of neurodegeneration in the Parkinsonian brain. If this mechanism is involved in the initiation of human Parkinson’s disease then we would expect that the pathologies associated with the disease would be initiated by this single insult. At present we are engaged in perfecting the technique of astrocyte ablation in addition to examining brain tissue to see if any associated pathologies have occurred as a result of astrocyte dysfunction. To date these have included, loss of dopaminergic neurons and metabolic changes as detected by cytochrome oxidase histochemistry. We will also examine for increased levels of active caspase 3 (marker for early apoptosis), TUNEL (late apoptosis) and complex I histochemistry (to examine for specific complex I deficit). We also need to know more about the nature of astrocytes in parts of the brain affected by Parkinsonian neurodegeneration, and so are in the process of investigating this cell type in more detail.
Truong L. Allbutt H. Kassiou M. Henderson JM. Developing a preclinical model of Parkinson's disease: a study of behaviour in rats with graded 6-OHDA lesions. Behavioural Brain Research. (2006)169(1):1-9
Allbutt HN. Henderson JM. Use of the Narrow Beam Test in the Rat, 6-hydroxydopamine model of Parkinson’s Disease. Journal of Neuroscience Methods. (2007) 159(2):195–202
Henderson JM. Schleimer SB. Allbutt H. Dabholkar V. Abela D. Jovic J. Quinlivan M. Behavioural effects of parafascicular thalamic lesions in an animal model of parkinsonism. Behavioural Brain Research. (2005) 162(2):222-32
Oehrn C. Allbutt HN. Henderson JM. Effect of ventrolateral thalamic nucleus lesions in the unilateral 6-hydroxydopamine rat model. Behavioural Brain Research (2007) 183(1):67-77
Leaver KR, Allbutt HN, Creber NJ, Kassiou M, Henderson JM. Oral pre-treatment with epigallocatechin gallate in 6-OHDA lesioned rats produces subtle symptomatic relief but not neuroprotection. Brain Research Bulletin (2009) In press