Objective/Rationale: IGF-1-mediated intracellular signaling pathways engage a wide range of potential survival mechanisms, the PI3K/Akt pathway and the ER stress response in particular, and it has been shown to exert broad neuroprotective effects in several models of neurological disorders and inflammatory conditions.
In addition, the IGF-1 receptor is highly expressed on midbrain DA neurons, and the levels of IGF-1 decrease in serum during aging compatible with a role in age-related neurodegenerative diseases.
Project Description:
We will study the biological response of nigral dopamine neurons to IGF-1 in basal conditions as well as in a scenario reminiscent to Parkinson’s disease such as oxidative stress and alpha-synuclein induced toxicity.
Gene therapy approach will tested in various models of Parkinson’s disease in order to ascertain whether IGF-1 can exert neuroprotection in pre-clinical models. Several intracellular pathways will be explored to identify potential mechanisms underlying the effect of IGF-1.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Despite that progressive loss of nigral dopamine neurons, results from the combination of pathogenic mechanisms, neurotrophic factors with pleiotropic effects have been poorly explored in pre-clinical models of Parkinson’s disease. Evaluating the effect of IGF-1 in well-established and complementary models of PD is an important step to determine the therapeutic potential of this trophic factor.
Anticipated Outcome:
If successful results are obtained in these relevant models, it will provide a strong proof-of-concept for testing for the use of IGF-1 gene therapy in patients with PD and for further development of IGF-1 receptors agonists or drugs promoting IGF-1 expression.
Final Outcome
The goal of this study was to determine whether IGF-1 gene transfer is a potential neuroprotective approach in two pre-clinical models of PD. We found that AAV-IGF delivery affords significant protection in the 6-OHDA MFB model as well as in the AAV-alpha-synuclein model of PD. In addition, pre-clinical models lacking the IGF-1 receptor specifically in nigral dopamine neurons were more sensitive to these insults. In summary, we provide evidence that IGF-1 gene therapy affords neuroprotection in two standard model of PD and supports the idea of targeting this pathway as a therapeutic approach.