Investigation of LRRK2 as a Regulator of Dendritic Cell Function

Promising Outcomes of Original Grant:
Myeloid cells (white blood cells) of the immune system include monocytes, neutrophils and dendritic cells found in circulation, as well as microglia (immune system cells) that reside within the central nervous system (CNS). Our original project focused on the role of LRRK2 in controlling the function of microglia, with the idea that cells lacking LRRK2 or harboring a mutant version of LRRK2, which are associated with familial (inherited) Parkinson's disease (PD), might show overactive immune function compared to cells bearing normal LRRK2. We designed experiments to investigate these issues using microglia cells and using a model of brain inflammation. These studies have yielded interesting results, not the least of which is that the role of LRRK2 may differ in different myeloid cell subsets.

Objectives for Supplemental Investigation:
Our follow up study will investigate how LRRK2 affects the function of one of the main myeloid cell type that resides outside the CNS - the dendritic cell (DC). DCs activate other cells of the immune system and LRRK2 appears to function quite differently. As DCs orchestrate the body's response to outside invaders such as infectious pathogens (e.g., viruses and bacteria), these studies have broad relevance to immune function in individuals with PD. Furthermore, we will investigate whether and how LRRK2 kinase inhibitors might alter the immune response in those taking these treatments.

Importance of This Research for the Development of a New PD Therapy:
A new group of molecules, known as LRRK2 kinase inhibitors, are under development for PD but their effects outside the brain, particularly on cells of the immune system that would be readily exposed to these compounds, remain unknown. The work to be undertaken in this extension project will shed important light on whether and how these compounds alter DC function.