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Investigation of LRRK2 as a Regulator of Microglial Cell Function

Objective/Rationale:             
Mutations of the LRRK2 gene are associated with Parkinson’s disease (PD), but very little is known about how or where the LRRK2 kinase normally functions in the brain. This project will investigate whether LRRK2 is important for restraining cells known as microglia, the main immune cell of the nervous system. Researchers hypothesize that PD-associated LRRK2 mutations disrupt this restraining effect, thereby resulting in overactive microglia and excessive inflammation that drive nerve cell degeneration to cause PD symptoms.

Project Description:
Microglial cells will first be isolated from the brains of pre-clinical models. A series of assays will then test whether deletion or mutation of LRRK2 alters the capacity of these cells in isolation to generate immune responses when compared to cells bearing normal LRRK2. Our next set of experiments will test whether models lacking LRRK2 or models carrying a mutated version of LRRK2 show altered microglia-dependent immune responses directly in the brain when compared to models bearing normal LRRK2. A series of assays to quantify brain inflammation will be performed in each group.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
Successful completion of these studies will for the first time: a) identify a specific function of LRRK2 in the brain, and b) quantify and compare how different LRRK2 mutations disrupt its normal function.

Anticipated Outcome:           
If LRRK2 proves to be important for controlling the function of microglial cells, this will highlight the importance of abnormal brain inflammation as a contributor to Parkinson’s disease. An important new framework to ask questions regarding the role of LRRK2 in Parkinson’s disease will emerge.


Researchers

  • David N. Irani, MD

    Ann Arbor, MI United States


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