Funded Studies
Study Rationale: In Parkinson’s disease (PD), the clumping of the protein alpha-synuclein in the brain causes the death of neurons. Recent studies have shown that the insulin-degrading enzyme (IDE) prevents alpha-synuclein aggregation in the pancreas. Although IDE is also abundant in the brain, it is not known if it offers neurons similar protection. IDE levels are reduced in the elderly and in people with diabetes, who are also at higher risk of developing PD. We have determined that IDE protects against alpha-synuclein toxicity in cellular models. However, its levels are decreased in the brains of mice with diabetes.
Hypothesis: We hypothesize that increasing the amount of IDE in the brain may arrest alpha-synuclein clumping, thereby protecting from neuronal loss. This strategy could therefore represent a novel therapeutic approach for PD.
Study Design: We propose to examine whether increasing IDE in the brain will prevent alpha-synuclein clumping and neurotoxicity, thereby alleviating PD-like symptoms in a preclinical mouse model of PD. We will feed animals either a standard diet or a diet rich in fat, which induces diabetes. First, we will assess whether diabetes aggravates PD-like symptoms, as it does in people with PD. We will then genetically boost IDE production in the brain, and see if this treatment can prevent, alleviate or arrest the onset and development of PD-like motor and non-motor changes, as well as prevent neuronal loss.
Impact on Diagnosis/Treatment of Parkinson’s disease: Our project has the potential to establish IDE as a disease-modulating therapeutic target for PD. Some compounds that are currently licensed for treating diabetes are known to increase IDE activity. These therapeutics could be readily repositioned or redesigned as a specific treatment for PD.
Next Steps for Development: In the future, we will evaluate the efficacy of IDE-enhancing drugs in preclinical models of PD.