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Identification of therapeutics that protect against toxins and genes implicated in Parkinson’s disease via the Forkhead-mediated transcription pathway

Loss of dopaminergic neurons is one of the cardinal features of Parkinson’s disease. Medications that can delay or prevent dopaminergic loss could be beneficial in treating PD, but the optimal therapeutic strategy has yet to be defined. Many investigators feel that damage from free radical play an important role in the disease process, but anti-oxidant therapy has so provided disappointing results from a clinical standpoint.

In this project we will explore a different strategy for neuroprotection. We propose to develop methods to induce the body’s own anti-oxidant defenses. Forkhead transcription factors induce production of numerous proteins that protect against damage associated with free radicals, such as is thought to occur in PD. The proteins induced by the forkhead pathway are particularly interesting because these proteins are designed to protect the mitochondria, which is the power generator of the cell. Our idea is that by stimulating the body’s own defenses, we can make an umbrella of protection around the mitochondria, to protect it from oxidative damage.

We will use two strategies for activating the forkhead transcription factors. Using cells that express proteins implicated in PD, we will assess the degree of protection provided by a panel of compounds previously shown to enhance activity of the forkhead transcription factors. We will compare these responses to those induced by a novel secreted protein that appears to be neuroprotective.

Final Outcome

This project focused on testing compounds that activated the forkhead transcription pathway in cell culture and C.elegans models of PD. Out of 44 compounds identified, two compounds inhibited rotenone-mediated toxicity as determined by cell based toxicity assays. However, these compounds did not activate foxo transcription when measured in a foxo reporter gene assay. In addition, Dr. Wolozin found that transfection of forkhead transcription factors were not protective in the models tested. Resveratrol showed protective properties in the cell and C. elegans models.

This work directly led to further studies examining protection against degeneration related to alpha-synuclein using SIRT1 agonists, which act in the same pathway as Forkhead. Dr. Wolozin and his group first demonstrated protection against degeneration related to alpha-synuclein by resveratrol. Next, they contacted the company Sirtris, who have made SIRT1 agonists. They have been successfully working with their compounds in C. elegans and are now investigating the efficacy in an MPTP pre-clinical model, in work also funded by MJFF. A manuscript detailing this information is currently in preparation.


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