LRRK2 Modulation and Neuroinflammatory Responses

Leucine‐rich repeat kinase 2 (LRRK2) has emerged as a pivotal regulator at the intersection of neurodegeneration and immune signalling. Originally identified through familial forms of Parkinson’s disease, LRRK2 is highly expressed in neurons, microglia and peripheral immune cells. Its kinase activity influences key pathways governing inflammation, cytoskeletal dynamics and vesicular trafficking. Dysregulation of LRRK2—whether by pathogenic mutations such as G2019S or by pharmacological inhibition—modulates the release of pro‐inflammatory cytokines, activation of microglia and infiltration of peripheral immune cells into the central nervous system. Such events contribute to a chronic neuroinflammatory milieu, exacerbating synaptic dysfunction and dopaminergic neurodegeneration. Beyond the brain, LRRK2 also shapes systemic inflammatory responses, linking gastrointestinal and hepatic inflammation to central immune changes. Recent advances have elucidated molecular mechanisms by which LRRK2-dependent phosphorylation events alter astrocyte and microglial behaviour, AQP4-mediated glymphatic clearance and blood–brain barrier integrity. These insights highlight LRRK2 as both a biomarker and a therapeutic target in disorders characterised by aberrant immune responses and neurodegeneration.

Research from Nature Portfolio

Foundational work has demonstrated how the G2019S mutation in LRRK2 impairs microglial motility by targeting focal adhesion kinase. Mutant microglia showed reduced process extension and delayed lesion isolation in response to brain injury, reflecting a direct impact on cytoskeletal regulators. Mechanistically, pathogenic LRRK2 binds and phosphorylates focal adhesion kinase at TXR/K motifs, attenuating its activation. Inhibition of LRRK2 kinase activity restored focal adhesion phosphorylation and rescued microglial dynamics. This study provided the first mechanistic link between LRRK2 mutations and compromised innate immune surveillance in the central nervous system.

LRRK2 Modulation and Neuroinflammatory Responses publication trend

The graph below shows the total number of articles in lrrk2 modulation and neuroinflammatory responses across all publications each year (not limited to Nature Index journals).

Technical terms

LRRK2: A multidomain kinase implicated in familial and sporadic Parkinson’s disease, involved in immune signalling and vesicle trafficking.

Neuroinflammation: The activation of glial cells and the release of pro-inflammatory mediators in the central nervous system.

Microglia: Resident immune cells of the brain that mediate surveillance, phagocytosis and inflammatory signalling.

Glymphatic system: A perivascular network facilitating the clearance of interstitial solutes from the brain via aquaporin-4 channels.

Kinase activity: The enzymatic transfer of phosphate groups to target proteins, modulating their function and signalling pathways.

References

1. LRRK2 G2019S mutation attenuates microglial motility by inhibiting focal adhesion kinase. Nature Communications (2015).
2. Mutant LRRK2 exacerbates immune response and neurodegeneration in a chronic model of experimental colitis. Acta Neuropathologica (2023).
3. Phosphorylation of AQP4 by LRRK2 R1441G impairs glymphatic clearance of IFNγ and aggravates dopaminergic neurodegeneration. npj Parkinson's Disease (2024).