LRRK2 Pathobiology in Neurodegenerative Disorders

Leucine-rich repeat kinase 2 (LRRK2) is a large multidomain enzyme combining GTPase and kinase functions that has emerged as a central player in the molecular cascades driving several neurodegenerative diseases, most prominently Parkinson’s disease. Pathogenic mutations, notably G2019S, enhance LRRK2 kinase activity, leading to abnormal phosphorylation of multiple substrates, including members of the Rab GTPase family. This hyperphosphorylation disrupts vesicle trafficking, synaptic vesicle fusion and neurotransmitter release, especially of dopamine, thereby compromising neuronal communication and viability. Concurrently, LRRK2 dysfunction perturbs mitochondrial dynamics, autophagic clearance and lysosomal function, fostering proteostatic stress and aggregation of proteins such as α-synuclein. Beyond neurons, aberrant LRRK2 signalling in glial and immune cells impairs inflammasome activation and wound-healing responses, exacerbating neuroinflammation and delaying tissue repair. Together, these insights highlight LRRK2 as a nexus linking intracellular trafficking, energy homeostasis and innate immunity, with broad implications for biomarker discovery and the development of targeted therapies.

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LRRK2 Pathobiology in Neurodegenerative Disorders publication trend

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Technical terms

Leucine-rich repeat kinase 2 (LRRK2): A large multidomain enzyme with both GTPase and kinase activities implicated in vesicle trafficking, autophagy and neuroinflammation.

Kinase activity: Enzymatic transfer of phosphate groups to protein substrates, regulating their function or localisation.

GTPase: Enzyme that hydrolyses guanosine triphosphate (GTP), acting as a molecular switch in signalling pathways.

Rab GTPases: A family of small GTP-binding proteins that control distinct steps of vesicle formation, movement and fusion.

Hyperphosphorylation: Excessive addition of phosphate groups to a protein, often altering its activity or interactions.

Inflammasome: A multiprotein complex in immune cells that activates inflammatory cytokines and triggers pyroptotic cell death.

Pyroptosis: An inflammatory form of programmed cell death driven by inflammasome activation and gasdermin cleavage.

Exosome-like vesicles: Small extracellular vesicles released by cells that carry proteins and signalling molecules to neighbouring or distant cells.

References

1. LRRK2G2019S Gene Mutation Causes Skeletal Muscle Impairment in Animal Model of Parkinson's Disease. Journal of Cachexia Sarcopenia and Muscle (2024).
2. Cellular and subcellular localization of Rab10 and phospho-T73 Rab10 in the mouse and human brain. Acta Neuropathologica Communications (2023).
3. The LRRK2-G2019S mutation attenuates repair of brain injury partially by reducing the release of osteopontin-containing monocytic exosome-like vesicles. Neurobiology of Disease (2024).
4. LRRK2 modifies α-syn pathology and spread in mouse models and human neurons. Acta Neuropathologica (2019).