Abstract
Links that implicate the gastrointestinal system in Parkinson’s disease (PD) pathogenesis and progression have become increasingly common. PD shares several similarities with Crohn’s disease (CD). Intestinal inflammation is common in both PD and CD and is hypothesized to contribute to PD neuropathology. Mutations in leucine-rich repeat kinase 2 (LRRK2) are one of the greatest genetic contributors to PD. Variants in LRRK2 have also been associated with increased incidence of CD. Since its discovery, LRRK2 has been studied intensely in neurons, despite multiple lines of evidence showing that LRRK2 is highly expressed in immune cells. Based on the fact that higher levels of LRRK2 are detectable in inflamed colonic tissue from CD patients and in peripheral immune cells from sporadic PD patients relative to matched controls, we posit that LRRK2 regulates inflammatory processes. Therefore, LRRK2 may sit at a crossroads whereby gut inflammation and higher LRRK2 levels in CD may be a biomarker of increased risk for sporadic PD and/or may represent a tractable therapeutic target in inflammatory diseases that increase risk for PD. Here we will focus on reviewing how PD and CD share overlapping phenotypes, particularly in terms of LRRK2 in the context of the immune system, that could be targeted in future therapies.
Highlights
The Leucine-rich repeat kinase 2 (LRRK2) gene has an important role in both sporadic and familial Parkinson’s disease (PD)
It may seem strange that LRRK2 is linked to an inflammatory disease of the gut when LRRK2 has been heavily studied in the context of PD; these two seemingly unrelated diseases are more related than we realize
The potential role of the gut in PD pathogenesis and pathophysiology has been thoroughly reviewed[9–11], and overwhelming evidence has led to the hypothesis that intestinal inflammation induced by multiple types of GI perturbations may promote peripheral inflammation that could contribute to neuroinflammation and neuropathology associated with PD
Summary
The Leucine-rich repeat kinase 2 (LRRK2) gene has an important role in both sporadic and familial Parkinson’s disease (PD). Several genome-wide association studies (GWAS) have identified that the LRRK2 gene is a common susceptibility locus for both PD and Crohn’s disease (CD), one of the inflammatory bowel diseases (IBD) that causes chronic inflammation of the gastrointestinal (GI) tract[2–7]. The potential role of the gut in PD pathogenesis and pathophysiology has been thoroughly reviewed[9–11], and overwhelming evidence has led to the hypothesis that intestinal inflammation induced by multiple types of GI perturbations may promote peripheral inflammation that could contribute to neuroinflammation and neuropathology associated with PD. We will review the evidence suggesting links between PD and CD and how the role of LRRK2 in the immune system may contribute to PD and CD and may provide rationale to target LRRK2 in inflammatory diseases
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