Leucine-rich repeat kinase 2 (LRRK2): balancing cellular homeostasis and Parkinson’s disease (PD) pathogenesis

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.