LRRK2 (Leucine-Rich Repeat Kinase 2), also known as LREK (a common misnaming), is one of the largest known protein kinases (2527 amino acids) and represents the most common genetic cause of familial Parkinson's disease (PD), accounting for 5-10% of autosomal dominant PD cases. The protein contains multiple functional domains including ROC (Ras of complex proteins) GTPase domain, COR (C-terminal of ROC) domain, and kinase domain, making it a unique signaling hub that integrates multiple cellular processes. Pathogenic LRRK2 mutations lead to enhanced kinase activity and subsequent neurotoxicity through mechanisms affecting autophagy, mitochondrial function, protein homeostasis, and synaptic transmission.
LRRK2 (Leucine-Rich Repeat Kinase 2), also known as LREK (a common misnaming), is one of the largest known protein kinases (2527 amino acids) and represents the most common genetic cause of familial Parkinson's disease (PD), accounting for 5-10% of autosomal dominant PD cases. The protein contains multiple functional domains including ROC (Ras of complex proteins) GTPase domain, COR (C-terminal of ROC) domain, and kinase domain, making it a unique signaling hub that integrates multiple cellular processes. Pathogenic LRRK2 mutations lead to enhanced kinase activity and subsequent neurotoxicity through mechanisms affecting autophagy, mitochondrial function, protein homeostasis, and synaptic transmission.
LRRK2 is the most common genetic cause of familial Parkinson's disease, encoding a large kinase with multiple functional domains. Pathogenic mutations, especially G2019S, lead to enhanced kinase activity and neurotoxicity through mechanisms involving autophagy impairment, mitochondrial dysfunction, and altered synaptic transmission. Therapeutic targeting of LRRK2 is an active area of drug development with multiple clinical candidates.
References
[Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron (2004)](https://doi.org/10.1016/j.neuron.2004.11.005)
[Paisán-Ruíz C, Jain S, Evans EW, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron (2004)](https://doi.org/10.1016/j.neuron.2004.10.023)
[Cookson MR. The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nature Reviews Neuroscience (2010)](https://doi.org/10.1038/nrn2935)
[Greggio E, Cookson MR. Leucine-rich repeat kinase 2 mutations and Parkinson's disease: three questions. Parkinsonism Relat Disord (2009)](https://doi.org/10.1016/j.parkreldis.2008.10.010)
[West AB, Moore DJ, Biskup S, et al. Parkinson's disease-associated mutations in LRRK2 link enhanced GTP binding and kinase activity to dopaminergic neuron degeneration. Neuron (2005)](https://doi.org/10.1016/j.neuron.2005.08.003)
[Dächsel JC, Farrer MJ. LRRK2 and Parkinson's disease: back to the future. Curr Opin Neurol (2010)](https://doi.org/10.1097/WCO.0b013e32833b1f5b)
[Jaleel M, Nichols RJ, Deak M, et al. LRRK2 phosphorylates moesin at Thr558: identification of a novel pathogenic PINK1 enzymatic cascade downstream of LRRK2. Biochem J (2007)](https://doi.org/10.1042/BJ20060757)
[Singleton AB, Farrer MJ, Bonifati V. LRRK2 gene in Parkinson disease: confusion of terminology. Lancet Neurol (2006)](https://doi.org/10.1016/S1474-4422(06)70525-0)
[Bellows ST, Jaleel M, Nichols RJ. Identification of LRRK2 membrane docking sites using synthetic lethal screens. Hum Mol Genet (2013)](https://pubmed.ncbi.nlm.nih.gov/23541299/)
[Daniel G, Moore DJ, Baker JE, et al. LRRK2 GTPase domain mutations and Parkinson's disease. J Parkinsons Dis (2015)](https://pubmed.ncbi.nlm.nih.gov/26577661/)
[Esteves AR, Swerdlow RH, Portugal MS, et al. LRRK2 and mitochondrial dysfunction in Parkinson's disease. J Neural Transm (2010)](https://pubmed.ncbi.nlm.nih.gov/20309610/)
[Gandhi PN, Chen SG, Wilson AL, et al. Oxidative stress activates LRRK2 kinase activity via autophosphorylation. J Biol Chem (2011)](https://pubmed.ncbi.nlm.nih.gov/21115494/)
[Greggio E, Cookson MR. The role of LRRK2 in Parkinson disease: a kinase at the hub of many filaments. Nat Rev Neurol (2012)](https://pubmed.ncbi.nlm.nih.gov/22814383/)
[Ibrahim F, Maraganore DM. LRRK2 mutations in Parkinson's disease: ethnic distribution and founder effects. J Neurol Sci (2013)](https://pubmed.ncbi.nlm.nih.gov/23597600/)
[MacLeod D, Dowling J, Hu J, et al. The familial Parkinson's disease gene LRRK2 regulates mitochondrial dynamics. Autophagy (2013)](https://pubmed.ncbi.nlm.nih.gov/23474760/)
[Marques O, Outeiro TF. LRRK2: function and dysfunction in cellular pathways. CNS Neurol Disord Drug Targets (2012)](https://pubmed.ncbi.nlm.nih.gov/23268661/)
[Meyer M, Liang Y, Rekha K, et al. LRRK2 in the protein quality control system: role of the ubiquitin-proteasome pathway. Mol Neurobiol (2013)](https://pubmed.ncbi.nlm.nih.gov/23516243/)
[Mueller ML, Stevens JA, Nucifora FC, et al. LRRK2 and protein aggregation in Parkinson's disease. Exp Neurol (2013)](https://pubmed.ncbi.nlm.nih.gov/23261954/)
[Nucifora FC, Burke K, Chen J, et al. The interplay between LRRK2 and autophagy in Parkinson's disease. Autophagy (2012)](https://pubmed.ncbi.nlm.nih.gov/22669201/)
[Su YC, Guo XZ, Cai KY, et al. LRRK2 and endolysosomal trafficking in Parkinson's disease. J Neurochem (2013)](https://pubmed.ncbi.nlm.nih.gov/23474760/)