SIRT1 Activators as Therapy for Parkinson's Disease

Objective/Rationale:
Resveratrol is a compound that activates a protetin, SIRT1, which is known to protect against stresses associated with neurodegeneration, including oxidative damage and protein misfolding. Despite its popular appeal, resveratrol suffers as a pharmacological compound because it is not absorbed by the body well. The biotechnology company Sirtris has recently developed other SirT1 activators with improved potency and bioavailability. We hypothesize that these compounds will provide protection in cellular and animal models of Parkinson’s disease.

Project Description: 
The first step of the project will determine whether the compounds made by Sirtris get into the brain. Based on these results we will select the compound with the best brain delivery for further study. The second step will determine whether the compounds protect in human nerve cells producing α-synuclein against toxicity and prevents alpha-synuclein clumping caused by the toxin, rotenone, which models Parkinson’s disease (PD). The third step will determine whether the Sitris compounds protect in a simple animal model of PD, nematodes that have been engineered to produce α-synuclein in their nerve cells. We will then treat the nematodes with rotenone, and examine the clumping of alpha-synuclein and nerve death associated with rotenone treatment. Finally, in the fourth step we will examine the effects of these compounds in a pre-clinical model of PD. We will treat mice with a toxic compound, termed MPTP, which causes death of the same population of nerve cells that die in PD, and determine whether the compounds protect against the toxicity of MPTP.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If these compounds protect in models of Parkinson’s disease, then they might ultimately be given as medication to patients with PD. I think that compounds might slow the loss of neurons associated with PD and help patients with PD retain their motor and thinking abilities.

Anticipated Outcome: 
We expect to learn the type of chemical structure that allows compounds to get into the brain, and yet still activate the protein SirT1. We also expect to determine whether activating this biochemical pathway can prevent against the nerve cell damage associated with PD. Finally, we expect to determine whether these compounds modify nerve cell damage by reducing the clumping of alpha-synuclein.