Objective/Rationale:
Patients with young onset Parkinson’s disease and patients with aged onset Parkinson’s disease differ in their course with young onset patients displaying a less malignant course and more treatment related side-effects. This grant plans to test the hypothesis than we can model these two subtypes of Parkinson’s disease by using a gene therapy approach that delivers a gene called alpha-synuclein, a gene known to cause Parkinson’s disease, to young and aged rats.
Project Description:
Young(3-4 month) and aged (21 month) rats will receive injections of a gene therapy approach that over expresses alphasynuclein into the substantia nigra. They will be tested behaviorally on a variety of tests including the stepping test, the cylinder test, and rotation test. We anticipate that young rats will display a slow decline while aged rats will display a more steep decline in motor function mimicking what is seen in young onset versus aged onset Parkinson’s disease. Then all rats will receive levodopa, the gold standard pharmacological treatment for Parkinson’s disease. We will determine whether young parkinsonian rats experience more levodopa related side effects compared to aged parkinsonian rat in a manner similar to young onset versus aged onset parkinsonism patients. Following the in life portion of this study, all animals will be sacrificed as we will determine whether viral over-expression of the alphasynuclein gene causes changes in the young brain different than those seen in the aged brain.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Many therapeutic strategies that are effective in animal models of Parkinson’s disease are not effective when tested in clinical trials. This may be due in part to the fact that the vast majority of therapies are tested in young animals while most Parkinson’s patients are older individuals. This studies aims to determine whether we can model young onset and old set Parkinson’s disease in animals which is better allow us in the future to test novel therapeutic strategies in the proper animal model.
Anticipated Outcome:
We anticipate that young rats administered the Parkinson’s disease gene alpha synuclein will result in a parkinsonian state that has a less malignant course but more treatment related side effects that administration of that same gene to aged rats.
Final Outcome
Young onset PD patients present with a less severe course of the disease but more treatment related side effects relative to their old-onset counterparts. In an effort to model this age-related dichotomy, we injected young (3-4 month old) and old (20 month old) rats bilaterally with a viral vector (AAV6) that delivered the gene for alpha synuclein or the control gene green fluorescent protein. Over the subsequent 16 week period, we examined four behaviors.
We found on the vibrissa test, which is a test of sensory-motor integration, that aged rats treated with AAV6-alphasynucleun displayed far greater behavioral deficits that their younger counterparts. On the cylinder test, which is a spontaneous motor assay, aged rats displayed small but significantly greater deficits than their younger counterparts. No differences between groups were seen on rotation on levo-dopa dyskinesias.
Both groups displayed robust expression of alpha-synuclein upon sacrifice. Surprisingly, all of the young rats had good lesions of the nigrostriatal system while none of the aged rats displayed a loss of nigrostriatal tome. These data suggest that aged rats, which normally display age-related alpha-synuclein may have developed a compensatory response to alpha-synuclein that prevented nigrostriatal degeneration and the behavioral changes observed are due to other non-DA mechanisms.