LRRK2 as a target for modulating immune system responses.

Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are associated with familial and sporadic cases of Parkinson's disease (PD) but are also found in patients with immune- related disorders, such as inflammatory bowel disease (IBD) and leprosy, linking LRRK2 to the immune system. Supporting this genetic evidence, in the last decade LRRK2 was robustly shown to modulate inflammatory responses at both systemic and central nervous system level. In this review, we recapitulate the role of LRRK2 in central and peripheral inflammation in PD and inflammatory disease models. Moreover, we discuss how LRRK2 inhibitors and anti- inflammatory drugs may be beneficial at reducing disease risk/progression in LRRK2-mutation carriers and manifesting PD patients, thus supporting LRRK2 as a promising disease-modifying PD strategy.

Disruption of LRRK2 in Zebrafish leads to hyperactivity and weakened antibacterial response.

As a protein with complex domain structure and roles in kinase, GTPase and scaffolding, LRRK2 is believed to be an important orchestration node leading to several cascades of signal transduction rather than one specific pathway. LRRK2 variants were found to be associated with Parkinson's disease, Crohn's disease and leprosy. Here we disrupt LRRK2 in zebrafish and found hyperactivity rather than hypoactivity in adult zebrafish mutants. By RNA-seq we found genes involved in infectious disease and immunological disease were notably affected. Functional studies also revealed a weakened antibacterial response in LRRK2 mutant. This mutant can be further explored for revealing molecular mechanisms and modeling of LRRK2 related diseases.

LRRK2 and the Immune System.

Polymorphisms in leucine-rich repeat kinase 2 (LRRK2) have been linked to familial Parkinson's disease, increased risk of sporadic Parkinson's disease, increased risk of Crohn's inflammatory bowel disease, and increased susceptibility to leprosy. As well as LRRK2 mutations, these diseases share in common immune dysfunction and inflammation. LRRK2 is highly expressed in particular immune cells and has been biochemically linked to the intertwined pathways regulating inflammation, mitochondrial function, and autophagy/lysosomal function. This review outlines what is currently understood about LRRK2 function in the immune system and the potential implications of LRRK2 dysfunction for diseases genetically linked to this enigmatic enzyme.

LRRK2 in peripheral and central nervous system innate immunity: its link to Parkinson's disease.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are found in familial and idiopathic cases of Parkinson's disease (PD), but are also associated with immune-related disorders, notably Crohn's disease and leprosy. Although the physiological function of LRRK2 protein remains largely elusive, increasing evidence suggests that it plays a role in innate immunity, a process that also has been implicated in neurodegenerative diseases, including PD. Innate immunity involves macrophages and microglia, in which endogenous LRRK2 expression is precisely regulated and expression is strongly up-regulated upon cell activation. This brief report discusses the current understanding of the involvement of LRRK2 in innate immunity particularly in relation to PD, critically examining its role in myeloid cells, particularly macrophages and microglia.

LRRK2 enhances Nod1/2-mediated inflammatory cytokine production by promoting Rip2 phosphorylation.

The innate immune system is critical for clearing infection, and is tightly regulated to avert excessive tissue damage. Nod1/2-Rip2 signaling, which is essential for initiating the innate immune response to bacterial infection and ER stress, is subject to many regulatory mechanisms. In this study, we found that LRRK2, encoded by a gene implicated in Crohn's disease, leprosy and familial Parkinson's disease, modulates the strength of Nod1/2-Rip2 signaling by enhancing Rip2 phosphorylation. LRRK2 deficiency markedly reduces cytokine production in macrophages upon Nod2 activation by muramyl dipeptide (MDP), Nod1 activation by D-gamma-Glu-meso-diaminopimelic acid (iE-DAP) or ER stress. Our biochemical study shows that the presence of LRRK2 is necessary for optimal phosphorylation of Rip2 upon Nod2 activation. Therefore, this study reveals that LRRK2 is a new positive regulator of Rip2 and promotes inflammatory cytokine induction through the Nod1/2-Rip2 pathway.