This grant builds upon the research from a prior grant: A Pre-clinical Alpha-Synuclein Model of Parkinson's Disease
Promising Outcomes of Original Grant:
In our previous grant, we attempted to create a bilateral model of PD using viral over expression of alpha-synuclein. The performance of the study was near perfect with DAT scan imaging, three behavioral tests, and neuroanatomical/neurochemical assessments performed in a timely fashion. However, there was a defect in the vector that limited expression. Thus we were unable to adequately test the original hypothesis
Objectives for Supplemental Investigation:
We will redo the original study. We will first test the vector and then perform a pilot experiment in two pre-clinical models monitoring the lesion using DAT SPECT scanning in vivo and analyzing post-mortem. We will then test the hypothesis that bilateral over-expression of AAV6-alpha synuclein will induce a behavioral syndrome as well as a time dependent nigrostriatal degeneration. We will also establish whether this model is sufficient to produce levodopa-induced dyskinesias.
Importance of This Research for the Development of a New PD Therapy:
This study will establish a more relevant model of PD.
Final Outcome
Alpha synuclein is a protein known to cause Parkinson’s disease. Many therapeutic strategies are based upon lowering the levels of alpha synuclein or preventing its transfer from cell to cell. We injected the substantia nigra on one side of non-human primates with a virus that encoded for alpha synuclein. We waited three months then sacrificed the non-human primates to determine whether we could produce a lesion similar to that seen in Parkinson’s disease. All non-human primates displayed human alpha synuclein in both the normal and pathological form. We established that non-human primates had a lesion of about 30-40% of dopamine neurons as well as a significant loss of dopamine in the striatum as measured by histology and neurochemistry. These data indicate that a non-human primate model based upon alpha synuclein pathology is possible.