Macrophage Precursors as Biomarker for LRRK2-associated Parkinson disease
Pharmacodynamic Biomarkers of LRRK2 Activity, 2010
LRRK2 mutations significantly contribute to the development of Parkinson Disease, a multisystem disorder. Neuronal loss is a prerequisite to develop the disease and a crosstalk between the brain and the immune system has been postulated. Assuming that immune cells are stimulated by and/or are attracted to the diseased brain we hypothesized that functional changes in these cells might be observed in the periphery and possibly indicate disease onset and progression. Here we investigate macrophage precursors as potential biomarker for LRRK2 associated disease.
In order to address our hypothesis we established a colony forming cell (CFC) assay as the most suitable assay to assess proliferation and differentiation in hematopoietic precursor cells. Using the CFC assay we assess the direct effect of secreted signaling proteins on hematopoiesis by counting erythroid, macrophage and granulocyte precursor cells. Our preliminary data suggest that the proportion of different precursor cells is altered in patients with PD, but also in preSymptoms & Side Effects LRRK2 mutation carriers, as compared to controls. Within this project we will be further testing the assay in cohorts of LRRK2 patients, preSymptoms & Side Effects LRRK2 mutation carriers and control individuals. To understand relevant pathways we will establish the assay in two, LRRK2 transgenic pre-clinical models. Finally we will use our read-out to test efficacy of LRRK2 specific inhibitors in pre-clinical and patient cells.
Relevance to Diagnosis/Treatment of Parkinsonís Disease:††
The aim of the study is to identify a biomarker that is closely linked to LRRK2 function. Up till now, no such biomarker is available. We propose that the colony forming cell assay has great potential to indicate and/or mirror pathogenic processes based on a constant crosstalk between the immune system and the brain. We expect that the assay will as well indicate pharmacological responses to therapeutic interventions.
We hope to understand more about the function of LRRK2 in the immune systems especially in monocytes and macrophages. Based on this understanding we want to monitor LRRK2 function in LRRK2 mutation carriers using blood derived cells as easy accessible cellular system. We hope to learn if LRRK2 function in monocytic cells is linked to Parkinson disease pathogenesis and also if we can use these cells to monitor disease progression and ideally also as drugable target.
We hypothesized changes in hematopoiesis in LRRK2 associated Parkinson disease. Therefore, we established a colony forming cell (CFC) assay to study hematopoietic stem cell differentiation from peripheral blood. Interestingly, we find a strong up-regulation in the production of macrophage precursors in LRRK2 associated Parkinson patients. Furthermore, we show that asymptomatic at high risk individuals have an increased percentage of macrophage precursors, comparable to that seen in LRRK2 patients. We speculate that these alterations in hematopoiesis are detectable years before onset of symptoms. In future studies we hope to show that easy accessible hematopoietic stem cells from peripheral blood are a potential dynamic biomarker to predict LRRK2 associated neurodegeneration in the brain.†
Director, Department of Neurodegeneration at Hertie Institute for Clinical Brain Research
Location: Tuebingen, Germany
Group Leader at Hertie Institute for Clinical Brain Research
Co-founder at Center for Genomics and Transcriptomics GmbH
Location: Tuebingen, Germany