Objective/Rationale:
Mitochondria are essential for generating energy for all the cells in the human body. Many human diseases are caused by malfunctions in mitochondria, including Parkinson’s disease. Understanding how neurons maintain mitochondrial health is essential to figure out how to prevent cell death that can lead to disease. The McQuibban lab has identified a protein called Rhomboid that may be crucial in regulating the life and death of neurons in people with Parkinson’s disease. Understanding how the Rhomboid protein functions will be important in designing potential therapeutics.
Project Description:
The McQuibban lab has recently identified that the mitochondrial Rhomboid protease undergoes a regulated cleavage that impacts mitochondrial activity. Lack of this cleavage may be implicated in neuronal cell death and Parkinson’s disease progression. With MJFF funding, we have three main objectives. First, we will determine whether Rhomboid cleavage is impaired in Parkinson’s patients, hopefully establishing a significant correlation. Second, we will determine the connection between Rhomboid cleavage, and mitochondrial health in neurons. Third, we will determine what the potential impact on cellular health is before and after Rhomboid cleavage. These studies will be carried out in well-controlled cultured cell models in the lab, to allow for timely and unambiguous evaluation of the experiments.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Parkinson’s disease is caused by the death of a selective set of neurons in the patient’s brain. The McQuibban lab has identified that a mitochondrial Rhomboid protease may be a causative factor in the disease. Two significant outcomes may result from the proposed research. First, a diagnostic tool, Rhomboid cleavage, may be discovered as a way to detect early signs of the disease. Second, regulating Rhomboid activity may be a way to prevent neuronal cell death to treat disease progression
Anticipated Outcome:
Understanding how neurons die during the progression of Parkinson’s disease is critical in designing therapeutics and eventually discovering a cure for the disease. The work that we will do over the next year with the Rhomboid protease will allow us to understand better a potential route of cell death, and with that, a way to design ways to prevent neurons from dying. Proteases are excellent drug targets and numerous small molecule libraries exist that can be tested for therapeutic efficacy.