Age-related Alterations in LRRK2 Expression and Function in Immune Cells and Risk for Idiopathic Parkinson's Disease
LRRK2 Role in Idiopathic Parkinson's Disease, 2014
The LRRK2 protein is highly expressed in immune cells, but its function is unknown and may change as the immune system changes with aging and environmental exposures, the largest risk factors for idiopathic (cause unknown) Parkinsonís disease (PD). This project will test the hypotheses that age-related alterations in LRRK2 levels or function skew the normal activity of innate and adaptive immune cells, uncouple key immune cell signaling pathways, and create a pro-inflammatory bias that triggers chronic neuroinflammation and may lead to increased risk for PD or accelerated disease progression.
Immune cell subtypes will be isolated from peripheral blood idiopathic PD patients and of age- and sex-matched controls. The frequency of monocytes and various T cell subsets and their activation markers and cytokine profiles will be correlated to LRRK2 expression. In the PD patients, correlations will be made to disease stage and severity. Lastly, coupling of LRRK2 to key immune cell signaling pathways will be measured and correlated to LRRK2 expression levels. While there are many other cell types that could contribute to PD origin and/or progression, by focusing on T cells and monocytes, we hope to gain the best insight into the potential role of LRRK2 in these cell types and their relationship to PD risk and/or progression.
Relevance to Diagnosis/Treatment of Parkinsonís Disease:
This study may reveal LRRK2 expression in specific immune cell subsets to be a novel PD-specific biomarker, which could serve in the testing of immune-based therapies already in development and clinical trials. If we find age- or PD stage-specific alterations in LRRK2 levels or in coupling between LRRK2 and key immune cell signaling pathways in subsets of immune cells, it may provide strong rationale for targeting LRRK2 function for neuroprotection.
If our hypothesis is correct, we expect to see age- and PD stage-related alterations in the frequencies of T cell subsets. Also, if LRRK2 is critical for monocyte activation responses, MHC II expression will be heightened with increased levels of LRRK2 in monocytes. Given that age is the greatest risk factor for idiopathic PD, findings that reveal age- related alterations in LRRK2 levels in immune cell subsets and/or uncoupling from key immune cell signaling pathways that dysregulate immune cell function may allow researchers to better understand the link between aging, environmental triggers that promote neuroinflammation and idiopathic PD.†
Associate Professor of Physiology at Emory University School of Medicine
Location: Atlanta, Georgia, United States