LRRK2 Physiology in Parkinson’s Disease


Date:            November 2011
Location:   Neuroscience Research Australia
Prof Glenda Halliday & Dr Nic Dzamko


Mutations in the LRRK2 gene are a common cause of genetic Parkinson’s 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 Parkinson’s disease as well as from pre-clinical models with genetically-modified LRRK2.

Project Description:

We aim to identify whether LRRK2 has a role in innate immune signaling, and whether its activity or phosphorylation is changed in Parkinson’s 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 Parkinson’s 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 Parkinson’s 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 Parkinson’s 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 Parkinson’s disease, we will assess this finding further as a potential biomarker for the disease.

Anticipated Outcome:

We know that LRRK2 mutations cause Parkinson’s 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 Parkinson’s disease, and we will determine whether LRRK2 in peripheral immune cells differs in patients with Parkinson’s disease from controls.