Although a number of genes have been identified that lead to Parkinson’s disease in humans, the scientific community has yet to be able to recapitulate this in pre-clinical models. One reason for this is that the pre-clinical model does not appear to “age”; and this difference between model and human may underlie the lack of parkinsonian symptoms. Using a transgenic pre-clinical model that has age-dependent changes to the basal ganglia we hope to generate a new pre-clinical model of alpha-synuclein induced parkinsonism.
We will cross a pre-clinical model lacking the anti-oxidant protein, glutathione S-transferase pi with a pre-clinical model that overexpress the A53T human alpha-synuclein protein. Previously we have shown that the A53T model has defects in the gut, but did not show CNS changes. In this new transgenic model cross, we will examine the interaction of ageing and A53T synuclein overexpression on substantia nigra dopaminergic cells number, straital dopamine, CNS inflammation and aggregation of alpha-synuclein
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
One of the goals of pre-clinical research is to generate pre-clinical models that recapitulate the pathology of human disease. So far, none of the familial PD pre-clinical models show a CNS pathology that is similar to that seen in humans. Thus, it is critical to develop such models. If successful, this model can be used in the generation and testing of drugs and other treatment that can slow, stop, or reverse the pathology seen in humans with Parkinson’s disease.
Based on preliminary studies, we expect to generate a pre-clinical model that better recapitulates the CNS pathology seen in humans with Parkinson’s disease. We expect to see an age-related decrease in SNpc dopamine neurons, increased number and activity of the innate immune system (microglia) and an increase in deposition of phosphorylated alpha-synuclein.
At this time, the total picture of the effects of the most common familial changes in the alpha-synuclein gene (known as A53T and A30P) and the role of oxidative stress on gene effects, is incomplete. Clearly, modulation of alpha-synuclein during normal ageing has an effect on the rate of DA neuron loss in the SNpc, and the addition of an oxidative background increases this effect.
We see a similar effect when examining levels of alpha-synuclein, although due to problems with specificity of reagents, we cannot comment on alterations in phosphorylation status.
In terms of an inflammatory response, changes in synuclein (A53T, A30P) appear to have either no effect, or lower expression of cytokines and chemokines at three months of age. This is interesting since we would have expected an increased inflammatory profile, but this is still an early stage of the study so we will continue to monitor progress over the next few months.