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LRRK2 Regulates Host Response to Microbial Infections

We recently formed a research team that comprises Parkinson’s scientists, immunologists, Crohn’s disease experts, virologists and pathologists; this, to explore a function for LRRK2 in the immune system. Several laboratories including ours determined that LRRK2 is highly expressed in circulating white blood cells of the macrophage/monocyte lineage. Our goal is to explore whether the association of LRRK2 with risk modulation of Parkinson disease, Crohn’s disease, and leprosy is based on a role in immune function.

Project Description:             
The main goal of our proposed work is to test whether LRRK2 function modifies the response by primary immune cells (such as macrophages) under culture conditions in a petri dish and by white blood cells in pre-clinical models after infection with different microbes (eg, bacteria and viruses). There, we will examine several LRRK2 variants (ie, normal LRRK2 protein vs. no protein at all vs. Parkinson’s-linked mutants). Our overarching hypothesis states that a second function of LRRK2 (in addition to that of a neuronal kinase) lies at the interface of host susceptibility, environment and tissue inflammation. We posit that this previously unrecognized role for LRRK2 is key to understanding the pathogenesis of LRRK2-associated illnesses in man, including PD [Mansoureh et al., J Neural Transm 2011)].

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
The biological function of LRRK2 remains unknown. Currently, it is widely considered to act as a kinase-type enzyme in nerve cells. The effect of some Parkinson’s-linked mutants (eg, G2019S) was shown to increase LRRK2’s kinase activity, which led to the identification of a new drug target candidate. Upon completion of our work, we hope to have shown that LRRK2 has a function in the immune system, which will undoubtedly inform efforts to develop inhibitors.

Anticipated Outcome:          
We anticipate that we will provide evidence that LRRK2’s function is involved in the response of an immune cell and, by inference of an entire organism, in the detection and successful clearing of a microbial entity. LRRK2 may clear bacteria or viruses through phagocytosis and lysosomal degradation. We believe that this previously unrecognized role for LRRK2 may be key to understanding the pathogenesis of LRRK2-associated illnesses in humans.


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