Objective/Rationale:
This project will aim to establish the behavioral and neuroanatomical correlates of injecting a viral vector that overexpresses the gene for alpha-synuclein into the brains of non-human primate pre-clinical models of PD. Alpha-synuclein is a protein whose mutation or overexpression is believed to play a role in Parkinson’s disease in humans. In rodents, injecting a virus that creates this protein causes cell death in the substantia nigra. This project will replicate and extend these findings in nonhuman primates.
Project Description:
We will test the hypothesis that a viral vector mediated over the expression of alpha-synuclein will produce a bilateral model of PD nigrostriatal degeneration and motor deficits in nonhuman primates. The time course of this degeneration will be tracked with Beta-CIT SPECT imaging. Toward this end, adult models will receive either bilateral intranigral injections of an adenoassociated virus (serotype 6; AAV6) encoding for mutant alpha-synuclein or control AAV6 injections. All models will be assessed preoperatively and postoperatively on Beta-CIT SPECT scanning, a hand-reach task, a clinical rating scale, general activity, and response to levodopa. Nine months post operatively, they will be sacrificed and assessed for: 1) extent of successful gene transfection using alpha-synuclein immunohistochemistry; 2) dopamine loss via HPLC for dopamine and metabolites; 3) stereological counts of TH-ir nigral neurons; 4) stereological counts of NeuN-ir nigral neurons; and 5) stereological counts of alpha-synuclein inclusions.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
To date, MPTP has been the gold standard model of Parkinson’s disease, especially in nonhuman primates. While MPTP can cause PD in humans, these cases are exceedingly rare and the relevance of MPTP to PD from a mechanistic standpoint is questionable. Mutation and overexpression of alpha-synuclein is a genetic cause of PD and alpha-synuclein is a major constituent of the Lewy body in all forms of PD. In rodents, over expression of alpha-synuclein causes nigrostriatal degeneration and motor deficits. Establishing a nonhuman primate model of alpha-synuclein over expression may be critical in establishing new therapies since some novel therapeutic strategies such as GDNF prevent nigrostriatal degeneration and motor deficits in virtually all models of PD except alpha-synuclein over expression.
Anticipated Outcome:
We expect to establish the time course of degeneration with a comprehensive functional and structural analysis to determine the value of viral over-expression of alpha-synuclein as a nonhuman primate model of Parkinson’s disease. We will also determine the ability of this model to establish treatment-related side effects such as levodopa dyskinesias.
Final Outcome
Dr. Kordower completed extensive work to generate and characterize a viral alpha-synuclein non-human primate model of PD. While no neuronal or behavioral changes were seen in the animals, results were inconclusive in that the virus used for the study demonstrated a lack of robust transfection efficiency.