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Therapeutic Development / Parkinson Disease · Journal article
Annals of Medicine · June 3, 2026
A consensus or society position rather than new primary data.
This is a narrative review synthesizing the current understanding of LRRK2 protein structure, normal cellular functions (autophagy, vesicular trafficking, mitochondrial dynamics, immune response), and mechanisms by which pathogenic LRRK2 mutations—particularly G2019S—may lead to dopaminergic neurodegeneration in Parkinson's disease. The review provides mechanistic context for LRRK2 dysregulation across neuronal and peripheral tissues but does not present primary empirical evidence or treatment outcomes.
Narrative review article. General population; PD patients; focus on LRRK2-related familial and sporadic Parkinson's disease.
PD affects 1–2% of population older than 60 years and 4% older than 85 years, with >6 million active cases reported worldwide in 2016 LRRK2 is a 286 kDa protein with 7 domains; G2019S is the most common genetic determinant of PD occurring in the kinase domain LRRK2 phosphorylates Rab GTPases (Rab8, Rab10, Rab29) regulating endolysosomal vesicle trafficking and lysosomal maturation
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Clinicians and researchers should use this review to understand the molecular mechanisms linking LRRK2 dysregulation to PD pathogenesis, particularly how kinase hyperactivity, vesicular trafficking disturbances, redox imbalance, and inflammation interact to drive neurodegeneration. This mechanistic foundation may inform future therapeutic targeting strategies, though no clinical trial data or treatment efficacy is presented.
A comprehensive narrative review synthesizing current understanding of LRRK2 biology and PD pathogenesis without primary empirical data or meta-analysis, providing mechanistic context for clinicians and researchers rather than practice-changing evidence.
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Clinicians and researchers should use this review to understand the molecular mechanisms linking LRRK2 dysregulation to PD pathogenesis, particularly how kinase hyperactivity, vesicular trafficking disturbances, redox imbalance, and inflammation interact to drive neurodegeneration. This mechanistic foundation may inform future therapeutic targeting strategies, though no clinical trial data or treatment efficacy is presented.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Background. Leucine-rich repeat kinase 2 (LRRK2) is a kinase with multi-signalling function that regulates various processes essential for neuronal and systemic physiology. It is involved in autophagy, vesicular trafficking, mitochondrial dynamics, and immune response. Pathogenic mutations of LRRK2 can significantly interfere with these physiological pathways essential for neuronal homeostasis, inducing degeneration of dopaminergic neurons-a characteristic feature of Parkinson's disease (PD).Objective. This review comprehensively summarizes the normal cellular functions of LRRK2 and the potential impact of its dysregulation on various physiological pathways, predisposing individuals to familial and sporadic PD. The mechanistic connections between LRRK2's kinase hyperactivity, disturbances in vesicular trafficking and redox status, systemic and neuronal inflammation, and metabolic disorders will be thoroughly discussed.Results. Dysregulation of vesicular trafficking, mitochondrial redox balance, inflammatory pathways, and metabolism promotes α-synuclein accumulation and contributes to the degeneration of nigrostriatal dopaminergic neurons, a central pathological feature of PD. Understanding the physiological role of LRRK2 across neuronal and peripheral tissues uncovers its connection with multiple pathways to maintain homeostasis. Its dysfunction disseminates local stresses into broader neurodegenerative changes.Conclusion. LRRK2 is implicated in multiple pathways that control neuronal integrity and neurodegeneration. Therefore, therapeutic targeting of LRRK2 could potentially help in restoring physiological function and management of PD.
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