Promising results from the University of Pittsburgh APDA Center for Advanced Research

Promising results from the University of Pittsburgh APDA Center for Advanced Research

J. Timothy Greenamyre, MD, PhD, University of Pittsburgh Medical Center

Building off of pivotal APDA-funded work highlighted here, Dr. J. Timothy Greenamyre and his team, published a investigating the role of Leucine-rich Repeat Kinase (LRRK2) in the development of Parkinson’s disease (PD). LRRK2 is known to be mutated in a small percentage of people with PD, about 1-2% of all people with PD, although much higher in certain populations, such as Ashkenazi Jews and North African Berbers. Dr. Greenamyre’s latest work is significant because together with his previous research, it indicates that reducing LRRK2 activation with medications could benefit a large number of people with PD. APDA is excited and inspired by the progress that comes from the research we fund and for the hope Dr. Greenamyre’s work brings to the PD community.

For background, LRRK2 is an enzyme, a protein used by the body to help bring about a biochemical reaction. Specifically, it is a kinase, an enzyme which adds phosphate groups onto other proteins. Mutations in LRRK2 that cause PD increase the kinase activity of LRRK2. LRRK2 has been shown to play a role in the endolysosomal system, the system within the cell that specializes in transporting and breaking down the cellular products that are no longer necessary. When this degradation system does not work properly, products can accumulate which can damage the cell.

In this new work, Dr. Greenamyre used a rat model of PD to characterize the deficits in the endolysosomal system that may be contributing to the disease state. He then treated these rats with a LRRK2 inhibitor which can pass through the blood-brain barrier. The treatment was shown to prevent the dysfunction in the endolysosomal system. In addition it promoted degradation of alpha-synuclein, which accumulates into structures known as Lewy bodies in PD. Finally, Dr. Greenamyre demonstrated that the LRRK2 inhibitor prevented neurodegeneration.

In previous work, Dr. Greenamyre showed that PD patients who did not have LRRK2 mutations also had increased activity of LRRK2. This means that LRRK2 activation is an important step in the development of PD and if the activation does not come via a mutation, it may come as a result of other biochemical changes in the cell. It also means that medications that reduce LRRK2 activation could help a large swath of patients with PD and not just people with a LRRK2 mutation. LRRK2 inhibitors are currently in clinical trial for their therapeutic effect in PD. This current study provides further rationale for pursuing this strategy as a treatment for PD and demonstrates the potential mechanisms by which a LRRK2 inhibitor might be beneficial to people with PD.

J. Timothy Greenamyre, PhD, Love Family Professor of Neurology in Pitt’s School of Medicine and director of the Pittsburgh Institute for Neurodegenerative Diseases (PIND) adds “There are several important findings from this work. First, our model system allows us to predict and replicate pathology seen in the brains of people with Parkinson’s. Because of this, we can test new therapeutic strategies with greater confidence that our experimental results can translate into clinical relevance. Most importantly, our work suggests that drugs that block LRRK2, some of which have entered clinical trials, will be useful for people with typical Parkinson’s disease,” Dr. Greenamyre is also the medical director of the APDA Center for Advanced Research at the University of Pittsburgh Medical Center and an esteemed member of the APDA Scientific Advisory Board.