LRRK2 Physiology in Parkinson's Disease
Mutations in the LRRK2 gene are a common cause of genetic Parkinsonís disease. LRRK2 is highly expressed in circulating and tissue immune cells. We have recently identified that LRRK2 is a component of the pathways involved in innate immunity. We aim to identify whether LRRK2 has a role in innate immunity using blood immune cells from donors with and without Parkinsonís disease as well as from pre-clinical models with genetically-modified LRRK2.
We aim to identify whether LRRK2 has a role in innate immune signaling, and whether its activity or phosphorylation is changed in Parkinsonís disease.
Signaling experiments will be performed using immune cells harvested from LRRK2 knockout models and controls (and LRRK1 knockouts in case of compensation). We will look for differences in the secretion of immune signaling molecules, gene expression and signal transduction. In separate experiments, we will modify immune pathways over 24 hours using drugs that activate different immune receptors and/or inhibit LRRK2 activity, and assess the same parameters.
Changes in Parkinsonís disease will be identified in immune cells isolated from donated venous blood samples from 30 patients and 30 matched controls recruited through specialized clinics. These cells will be cultured under sterile conditions and the amount of phosphorylated and total LRRK2, LRRK2 activity and gene expression determined.
Relevance to Diagnosis/Treatment of Parkinsonís Disease:
These studies will provide basic information on whether LRRK2 plays a role in innate immunity, and whether LRRK2 is changed in peripheral immune cells in patients with Parkinsonís disease. Our signaling experiments will identify potentially modifiable immune pathways for future therapeutic targeting. If we observe a change in LRRK2 only in immune cells from patients with Parkinsonís disease, we will assess this finding further as a potential biomarker for the disease.
We know that LRRK2 mutations cause Parkinsonís disease, but how is still poorly understood. LRRK2 is highly expressed in immune cells, and we will determine whether LRRK2 plays a role in innate immunity by harvesting the immune cells from knockout and control pre-clinical models and comparing their normal functioning. It is currently unknown whether LRRK2 activity or phosphorylation is altered in Parkinsonís disease, and we will determine whether LRRK2 in peripheral immune cells differs in patients with Parkinsonís disease from controls.
Our investigation into the physiological function of LRRK2 has uncovered a number of potential roles for this protein in regulating aspects of the inflammatory response to foreign pathogens. By testing a number of stimuli to mimic different kinds of bacterial or viral infections we have narrowed down a possible function of LRRK2 in a pathway known as the toll-like receptor (TLR) pathway. This pathway is a major regulator of pro-inflammatory cytokines (small signaling proteins), factors often increased in Parkinsonís disease patients. We have found differences in TLR-mediated inflammation when using drugs to block LRRK2 in cells or by studying cells deficient in LRRK2. These results provide clues to the role of LRRK2 in immune cells and they may have further implications for understanding Parkinsonís disease. We also explored whether Parkinsonís disease patients had more LRRK2 in their peripheral immune cells. Our results suggest that LRRK2 is not different between Parkinsonís patients and control subjects.††
Senior Principal Research Fellow at University of Sydney
Location: Sydney, Australia
Senior Research Fellow at The University of Sydney
Location: Sydney, Australia