Leucine-rich repeat kinase 2 (LRRK2)
Synonyms: PARK8, dardarin
Missense mutations in LRRK2 were first identified as a cause of Parkinson’s disease (PD) in 2004. Subsequent studies showed that these mutations account for up to 10 percent of familial cases, with even higher prevalence in Ashkenazi Jewish and North African Arab populations. In addition, polymorphic LRRK2 variants occur in about 2 percent of sporadic cases, making LRRK2 one of the most common PD genes. Candidate gene and genome-wide association studies have identified many LRRK2 variants in PD patients; of those, Gly2019Ser is the most common of six variants known thus far to be pathogenic. LRRK2 currently ranks fourth on PDGene.
LRRK2 missense mutations have an autosomal-dominant inheritance pattern. Unlike the APP or PS1 pathogenic Alzheimer’s mutations, whose penetrance is nearly complete, LRRK2 mutation penetrance is incomplete and highly variable. PD develops in 25 to 80 percent of LRRK2 mutation carriers, depending on the study sample. LRRK2-associated Parkinson’s first becomes symptomatic across a wide age range, but its clinical progression and pathology closely resemble that of idiopathic PD. Additionally, lrrk2 protein levels are elevated in sporadic PD.
LRRK2 is expressed throughout the brain in both neurons and microglia. Microglial expression rises in response to infection and inflammation. LRRK2 is also expressed in circulating immune cells, pointing to a role in innate immunity. Indeed, LRRK2 has also been linked to Crohn’s and other inflammatory bowel diseases.
Leucine-rich repeat kinase 2 encodes a large, complex protein containing a kinase, a GTPase, and multiple protein-protein interaction domains. The interplay of its enzymatic kinase and signaling GTPase domains remains unknown. The G2019S LRRK2 mutation increases lrrk2’s kinase activity, but other pathogenic variants have different effects, including dampening kinase or GTPase activity. Animal and cell culture studies have linked lrrk2’s kinase activity to toxicity, and kinase inhibitors are being pursued as a therapeutic strategy for PD. Even so, the role of the kinase remains controversial; other groups have found that toxicity depends instead on the cellular concentration of lrrk2 protein.
Lrrk2 has been implicated in numerous cellular processes, particularly protein trafficking, recycling of synaptic and Golgi vesicles, mitophagy, and autophagy, but the overall physiological function and regulation of LRRK2 is not clear. Lrrk2 promotes the accumulation of a-synuclein deposits by an unknown mechanism, and evidence shows that autophagy slows in cells expressing pathogenic LRRK2 variants. Exactly how mutations predispose to Parkinson’s disease remains poorly understood a decade after LRRK2’s discovery as a PD gene, in part because rodent models of LRRK2 recapitulate aspects of PD, but not the full disease.
LRRK2 has become a central focus of Parkinson’s research. At the molecular level, points of interaction with other PD genes are being studied to establish pathways of pathogenesis. At the human research level, a large longitudinal cohort study tracks mutation carriers in several populations worldwide to characterize the preclinical stages of pathology and to find biomarkers that predict disease progression.
- PARK8 is Cloned: Introducing…"Dardarin"
- Not Just a Family Affair: Dardarin Mutations Predict Sporadic PD
- More Than a LRRK: PD Field Thinks Big With Genetic Cohort
- Evidence Piles Up for Lysosomal Dysfunction in Parkinson’s
- New Substrate for Parkinson’s Protein Is Picky About Phosphate
- The Many Faces of LRRK2
- LRRK Watchers’ Eyes Turn to Inflammation, Autophagy, Kinase
- Rethinking LRRK2 Toxicity: It’s How Much Is Present, Not What It Does
- LRRK2 Interactions Identify New Parkinson’s Genes, Implicate Autophagy
- Hyun CH, Yoon CY, Lee HJ, Lee SJ. LRRK2 as a Potential Genetic Modifier of Synucleinopathies: Interlacing the Two Major Genetic Factors of Parkinson's Disease. Exp Neurobiol. 2013 Dec;22(4):249-57. Epub 2013 Dec 31 PubMed.
- Chan SL, Angeles DC, Tan EK. Targeting leucine-rich repeat kinase 2 in Parkinson's disease. Expert Opin Ther Targets. 2013 Dec;17(12):1471-82. Epub 2013 Nov 9 PubMed.
- Tsika E, Moore DJ. Contribution of GTPase activity to LRRK2-associated Parkinson disease. Small GTPases. 2013 Jul-Sep;4(3):164-70. Epub 2013 Jun 10 PubMed.
- Rideout HJ, Stefanis L. The Neurobiology of LRRK2 and its Role in the Pathogenesis of Parkinson's Disease. Neurochem Res. 2013 Jun 1; PubMed.
- Dzamko N, Halliday GM. An emerging role for LRRK2 in the immune system. Biochem Soc Trans. 2012 Oct;40(5):1134-9. PubMed.
- Sloan M, Alegre-Abarrategui J, Wade-Martins R. Insights into LRRK2 function and dysfunction from transgenic and knockout rodent models. Biochem Soc Trans. 2012 Oct;40(5):1080-5. PubMed.