Grant: Project Grant

Parkinson's disease (PD) is a common brain disorder that causes tremor, stiffness, slowed movements, and eventually problems with thinking and memory. These symptoms are linked to the buildup of a protein called alpha-synuclein (aSyn), which clumps inside brain cells, and to the loss of dopamine-producing neurons. Current treatments relieve symptoms but do not stop the disease. Our research focuses on a gene called Rit2, which helps brain cells clear waste and maintain communication. Large genetic studies have linked Rit2 to PD, and our work showed that increasing Rit2 in dopamine neurons can protect against damage caused by aSyn. However, boosting Rit2 too much can disrupt normal activity. This means we need a way to restore Rit2 to the right level. To achieve this, we are developing a new type of gene therapy using "SINEUPs." These molecules increase the amount of a specific protein by about two-fold, matching the decrease seen in PD brains. This provides a gentle and controlled way to restore Rit2 without harmful side effects. In Aim 1, we will test whether restoring Rit2 can protect human brain cells grown in the lab from patients with PD. These "organoids" mimic features of the disease and will allow us to study Rit2's effects. In Aim 2, we will test Rit2 restoration in a mouse model that develops widespread aSyn pathology and movement problems. We will use a specially designed viral vector that crosses the blood-brain barrier, allowing Rit2 to be restored across the brain with a simple intravenous injection. This will let us test both early (preventive) and late (therapeutic) strategies. We will also study how Rit2 protects the brain by examining its impact on dopamine signaling, protein recycling pathways, and another PD-linked protein called LRRK2. By combining human and animal models, this project will reveal how Rit2 protects the brain and establish a new gene therapy strategy aimed at slowing or stopping the progression of PD.