LRRK2, or leucine-rich repeat kinase 2, is a complex protein with a RocCOR tandem (possessing GTPase activity) and a kinase domain, along with several other domains involved in protein-protein interactions [3]. It plays crucial roles in multiple cellular processes such as cytoskeletal dynamics, endolysosomal pathway, membrane and vesicle trafficking, autophagy, and lysosome biology [6,8]. Mutations in LRRK2 are the most common cause of familial Parkinson's disease (PD) and are associated with a significant proportion of sporadic PD cases, making it an attractive genetic model for PD research [2,5].

Pathogenic LRRK2 mutations generally increase its kinase activity, which may lead to a toxic hyperactive protein and the PD phenotype [4]. LRRK2 has been linked to endolysosomal system functions, where it is regulated by and regulates Rab GTPases [2]. It is also recruited to and activated at stressed or damaged lysosomes through an interaction with GABARAP via the CASM pathway [7]. In PD, LRRK2-PD has a generally benign clinical presentation and variable pathology, with inconsistent Lewy bodies and marked Alzheimer's disease-like pathology [1].

In conclusion, LRRK2 is essential in multiple cellular pathways, especially those related to membrane trafficking and lysosomal function. The study of LRRK2, particularly through genetic models like in PD research, helps us understand the complex mechanisms underlying PD and may provide potential therapeutic targets for this neurodegenerative disease.

References:

1. Sosero, Yuri L, Gan-Or, Ziv. 2023. LRRK2 and Parkinson's disease: from genetics to targeted therapy. In Annals of clinical and translational neurology, 10, 850-864. doi:10.1002/acn3.51776. https://pubmed.ncbi.nlm.nih.gov/37021623/

2. Usmani, Ahsan, Shavarebi, Farbod, Hiniker, Annie. 2021. The Cell Biology of LRRK2 in Parkinson's Disease. In Molecular and cellular biology, 41, . doi:10.1128/MCB.00660-20. https://pubmed.ncbi.nlm.nih.gov/33526455/

3. Zhang, Xiaojuan, Kortholt, Arjan. 2023. LRRK2 Structure-Based Activation Mechanism and Pathogenesis. In Biomolecules, 13, . doi:10.3390/biom13040612. https://pubmed.ncbi.nlm.nih.gov/37189360/

4. Bonet-Ponce, Luis, Cookson, Mark R. 2021. LRRK2 recruitment, activity, and function in organelles. In The FEBS journal, 289, 6871-6890. doi:10.1111/febs.16099. https://pubmed.ncbi.nlm.nih.gov/34196120/

5. Xiong, Yulan, Yu, Jianzhong. 2024. LRRK2 in Parkinson's disease: upstream regulation and therapeutic targeting. In Trends in molecular medicine, 30, 982-996. doi:10.1016/j.molmed.2024.07.003. https://pubmed.ncbi.nlm.nih.gov/39153957/

6. Iannotta, Lucia, Greggio, Elisa. . LRRK2 signaling in neurodegeneration: two decades of progress. In Essays in biochemistry, 65, 859-872. doi:10.1042/EBC20210013. https://pubmed.ncbi.nlm.nih.gov/34897411/

7. Bentley-DeSousa, Amanda, Clegg, Devin, Ferguson, Shawn M. 2025. LRRK2, lysosome damage, and Parkinson's disease. In Current opinion in cell biology, 93, 102482. doi:10.1016/j.ceb.2025.102482. https://pubmed.ncbi.nlm.nih.gov/39983584/

8. Piccoli, Giovanni, Volta, Mattia. . LRRK2 along the Golgi and lysosome connection: a jamming situation. In Biochemical Society transactions, 49, 2063-2072. doi:10.1042/BST20201146. https://pubmed.ncbi.nlm.nih.gov/34495322/