Hsp90 as a Target for Neuroprotective Agents in Parkinson's Disease

Objective/Rationale: 
Cell death caused by alpha-synuclein aggregation is thought to play a central role in the pathogenesis of Parkinson’s disease. Previous studies have found that a class of compounds called Hsp90 inhibitors can lead to an increase in protective chaperone proteins and prevent alpha-synuclein aggregation and its associated cell death in cells in culture. This project will investigate if these results can translate to animals and will study if Hsp90 inhibitors can rescue cells from death in a pre-clinical model of Parkinson’s disease.

Project Description:
We will use a rodent viral-vector model of Parkinson’s disease whereby the substantia nigra region of rodents is injected with a viral vector that expresses the protein alpha-synuclein. The targeted overexpression of alpha-synuclein in the rodent brain has been shown to produce the death of neurons in the injected region. Following viral vector injections, we will treat the rodents with novel Hsp90 inhibitors for six weeks. These inhibitors cause an increase in the amount of protective chaperone proteins in the brain and will be given orally because they can cross the blood brain barrier. After six weeks we will examine the rodent brains to determine if the Hsp90 inhibitors have been able to prevent the cell death that is normally caused by the overexpression of alpha-synuclein.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If Hsp90 inhibitors are successful in preventing cell death in animal models of Parkinson’s disease they would represent a novel class of drugs that have the potential to be a treatment for the disease. Treatment with Hsp90 inhibitors could potentially protect the brain from cell death and thus halt the further progression of the disease.
Anticipated Outcome: 
We anticipate that, if successful, this project will affirm that Hsp90 inhibitors can protect against alpha-synuclein-induced cell death in an animal model of Parkinson’s disease by increasing the amount of protective chaperone proteins in the brain. This result would be significant because it would identify Hsp90 inhibitors as an important therapeutic strategy for treatment of the disease and support the development of these drugs for the treatment of Parkinson’s disease by major pharmaceutical companies.