Leucine-rich repeat kinase 2 (LRRK2) has emerged as a critical player in both neurological and peripheral diseases. In a comprehensive review, researchers from Sichuan University examine the diverse cellular functions of LRRK2, its pathogenic mechanisms in Parkinson's disease and other disorders, and recent advances in LRRK2-targeted therapies. The review highlights how LRRK2 mutations disrupt intracellular signaling, mitochondrial function, and lysosomal homeostasis, while also exploring the therapeutic potential of LRRK2 kinase inhibitors currently under clinical development.
Since its discovery as a key genetic factor in Parkinson's disease (PD) in 2004, LRRK2 has become one of the most intensely studied proteins in neurodegenerative disease research. However, scientists have increasingly recognized that LRRK2's influence extends far beyond the central nervous system, playing important roles in the kidneys, lungs, immune system, and even cancer development.
To provide a comprehensive overview of this multifaceted protein, Professor Xiawei Wei and colleagues from the Department of Biotherapy at West China Hospital, Sichuan University, conducted an extensive review of LRRK2 research. Their work synthesizes current knowledge on LRRK2's physiological functions, its pathogenic mechanisms across multiple diseases, and the rapidly evolving landscape of LRRK2-targeted therapeutics. The review was published in the Chinese Medical Journal on March 05, 2026.
"LRRK2 is not just a regulator of central nervous system activity but a key player found throughout multiple organs and systems, where it helps maintain normal physiological function," explains Prof. Wei, corresponding author of the study. "Understanding its tissue-specific effects is crucial for developing targeted therapies."
LRRK2 is a large, multifunctional protein with both kinase and GTPase activities. Under normal physiological conditions, it regulates essential cellular processes including membrane transport, lysosomal function, mitochondrial homeostasis, and immune responses through interactions with specific Rab proteins such as Rab29 and Rab32. These interactions modulate intracellular signaling and maintain cellular health.
However, pathogenic LRRK2 mutations—particularly the common G2019S mutation—disrupt these finely tuned processes. The review details how such mutations lead to multiple cellular dysfunctions: impaired autophagosome transport causing accumulation of metabolic waste, lysosomal abnormalities affecting protein degradation, mitochondrial dysfunction with reduced energy production, and disrupted immune regulation. These mechanisms not only drive neurodegeneration in PD but also contribute to inflammatory diseases like Crohn's disease, pulmonary fibrosis, and even certain cancers.
Interestingly, LRRK2 exhibits tissue-specific and context-dependent effects. While LRRK2 mutations promote neurodegeneration in the brain, reduced LRRK2 expression is associated with lung cancer progression, and elevated LRRK2 levels correlate with poor prognosis in ovarian cancer. This complexity highlights the importance of understanding LRRK2's diverse biological roles.
The review places special emphasis on therapeutic strategies targeting LRRK2. Several LRRK2 kinase inhibitors have shown promise in preclinical studies, with DNL151 (BIIB122) and DNL201 (GNE0877) currently advancing through clinical trials for PD. These inhibitors work by stabilizing the open conformation of LRRK2, reducing its interference with microtubules and normalizing cellular function.
"Inhibiting LRRK2 kinase activity shows potential for treating PD by correcting cellular imbalances and reducing neuronal damage," notes Prof. Wei. "However, risks associated with regulating a multifunctional protein must be carefully addressed."
The review also explores emerging therapeutic approaches beyond traditional kinase inhibitors, including PROTACs for targeted LRRK2 degradation, antisense oligonucleotides, and gene therapy strategies. These innovative approaches may offer improved selectivity and reduced off-target effects.
Despite significant progress, challenges remain. Poor blood-brain barrier penetration has limited the CNS efficacy of early inhibitors, and long-term safety concerns persist regarding peripheral organ effects. The authors emphasize the need for enhanced brain delivery, improved selectivity, and personalized approaches guided by genetic profiling and dynamic biomarkers.
"Future investigations will focus on how to use this knowledge to develop treatment strategies targeting LRRK2, providing more effective treatment options for patients with PD and inflammatory diseases," concludes Prof. Wei. "As our understanding of LRRK2's functions and its role in diseases deepens, new therapeutic methods will continue to emerge, heralding new hope to patients."
This comprehensive review not only synthesizes current knowledge but also identifies key unanswered questions, providing valuable guidance for future research directions in LRRK2 biology and therapeutic development.
***
About Professor Xiawei Wei from Sichuan University
Professor Xiawei Wei is Principal Investigator at State Key Laboratory of Biotherapy and Deputy Director of National Clinical Research Center for Geriatrics at West China Hospital, Sichuan University. She serves on committees of the American Society of Gene and Cell Therapy and is Youth Chair of the Asia–Pacific Society for Gene and Cell Therapy. Prof. Wei sits on editorial boards of five SCI-indexed journals and has authored over 40 publications. Her research focuses on cancer vaccines, anti-aging drug development, and mitochondrial immune regulation. She earned her PhD from Sichuan University and was a visiting scholar at University of Tokyo.
Funding information
This work was supported by the National Key Research and Development Program of China (No. 2024YFC2310700) and the 1·3·5 project for disciplines of excellence—Clinical Research Fund, West China Hospital, Sichuan University (No. ZYGD23038).
Chinese Medical Journal
Literature review
Cells
Role of LRRK2 in physiological activities, diseases, and therapy
5-Mar-2026
None