Does Peripheral Immune Challenge Exacerbate LRRK2-Induced Neuronal Pathology?
LRRK2 in the Immune System, 2012
Neuro-immune interactions may have etiological roles in the development of several neurodegenerative disorders. LRRK2 is a cell signaling protein and when mutated, is the most frequent gene associated with inherited Parkinsonís disease (PD) in humans. LRRK2 has recently also been highlighted as a mediator of immune system function. We believe that aberrant interactions between mutant LRRK2 and the immune system may modify disease onset in PD. In this project we will determine how a systemic infection can influence neural dysfunction and degeneration in LRRK2 transgenic pre-clinical models.
We will use transgenic pre-clinical models that either express mutant R1441G LRRK2 (a PD-associated mutation) or models that have a knockdown of normal LRRK2. We will induce a systemic infection using a synthetic viral-mimic called poly(I:C). At different time points following the inflammatory poly(I:C) challenge we will use functional tests to examine changes in the peripheral and central nervous systems. These will include assessment of gastrointestinal function (e.g. constipation), motor impairment and cognitive deficits. At post-mortem we will determine in both the gastrointestinal tract and brain, whether PD-like pathology, neuroinflammation, and neurodegeneration are altered by the systemic inflammation in the mutant LRRK2 and LRRK2 knockout model.
Relevance to Diagnosis/Treatment of Parkinsonís Disease:†††††††††††††††††††††
We hypothesize that neuroinflammatory challenges (e.g. common cold and flu viruses, viral encephalitis, chronic inflammatory disease) that induce expression of inflammatory molecules in the periphery and in the brain, combined with a second insult (e.g. LRRK2 genetic susceptibility), could underlie both the initiation and the patterns of relative neuronal vulnerabilities in PD. The experiments proposed in this project will determine how a systemic viral-like challenge can influence the development of LRRK2-induced neuronal dysfunction and pathology in the central and peripheral nervous systems, both of which are affected in PD in humans. We will examine the overall role of both mutant and normal LRRK2 in mediating inflammatory responses and PD-like degeneration. These data will provide important conclusions about the role of LRRK2 in mediating immune responses and neurodegeneration in PD.
We will learn how mutant LRRK2 and LRRK2 knockdown can modify the bodyís peripheral and brain responses to a systemic inflammatory challenge. We will determine whether LRRK2 transgenic pre-clinical models demonstrate altered neurodegenerative profiles in the gastrointestinal tract and brain following viral-like inflammation.
Assistant Professor of Psychiatry and Director, Neuroregeneration Institute at Harvard Medical School/McLean Hospital
Location: Belmont, Massachusetts, United States