Function Of LRRK2 Research Articles

Ancient Origin of the Parkinson Disease Gene LRRK2

Dominant mutations in the LRRK2 gene, a member of the Roco family, cause both familial and sporadic Parkinson disease. LRRK genes had so far been detected only in bilaterian animals. In deuterostomes, including humans, two LRRK genes (LRRK1 and LRRK2) exist, while in protostomes a single LRRK gene has been found. In this study, I combine structural and phylogenetic analyses to show that the cnidarian Nematostella vectensis has four LRRK genes. One of them is a bona fide orthologue of the human LRRK2 gene, demonstrating that this gene has an ancient origin. Two others are, respectively, orthologues of the deuterostome LRRK1 and the protostome LRRK genes. The fourth gene is probably cnidarian-specific. This precise characterization of the early evolution of LRRK genes in animals has important implications, because it indicates that the Drosophila and Caenorhabditis LRRK genes, which are studied to gain an understanding of LRRK2 function, are not true orthologues of the human Parkinson disease gene. Novel functional insights are also gained by comparison of the structures of LRRK2 genes in distantly related species.

Dispensable role of Drosophila ortholog of LRRK2 kinase activity in survival of dopaminergic neurons

BackgroundParkinson's disease (PD) is the most prevalent incurable neurodegenerative movement disorder. Mutations in LRRK2 are associated with both autosomal dominant familial and sporadic forms of PD. LRRK2 encodes a large putative serine/threonine kinase with GTPase activity. Increased LRRK2 kinase activity plays a critical role in pathogenic LRRK2 mutant-induced neurodegeneration in vitro. Little is known about the physiological function of LRRK2.ResultsWe have recently identified a Drosophila line with a P-element insertion in an ortholog gene of human LRRK2 (dLRRK). The insertion results in a truncated Drosophila LRRK variant with N-terminal 1290 amino acids but lacking C-terminal kinase domain. The homozygous mutant fly develops normally with normal life span as well as unchanged number and pattern of dopaminergic neurons. However, dLRRK mutant flies were selectively sensitive to hydrogen peroxide induced stress but not to paraquat, rotenone and β-mercaptoethanol induced stresses.ConclusionOur results indicate that inactivation of dLRRK kinase activity is not essential for fly development and suggest that inhibition of LRRK activity may serve as a potential treatment of PD. However, dLRRK kinase activity likely plays a role in protecting against oxidative stress.

P.5.d.001 Expression of alpha-synuclein in patients with Parkinson's disease caused by mutations in the LRRK2 gene

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene were initially identified in large families with autosomal dominant Parkinson disease (PD). These mutations (p.R1441C, p.R1441G, p.Y1699C and p.I2020T) revealed that genetic mutations could cause clinically typical, late-onset PD. Subsequently, the p.G2019S mutation was found to be a frequent cause of both autosomal dominant and “sporadic” PD, particularly in populations in North Africa or the Middle East. Two Lrrk2 protein substitutions (p.R1628P and p.G2385R) have since been associated with susceptibility to PD in Asian populations. More than a hundred variants have been identified in the LRRK2 gene, but pathogenicity is most convincing for the p.R1441H substitution. The role in PD remains unknown for other variants because segregation with disease has not been shown. Screening these variants in very large patient-control series may help clarify their role in PD. Lrrk2 is a large, multidomain protein with pathogenic mutations occurring in several functional domains. Cell biological experiments have shown that the p.G2019S mutation increase kinase activity. This is consistent with the observation that homozygous p.G2019S carriers do not have earlier disease onset or more severe disease compared with heterozygous carries. It is now necessary to identify the regulators and substrates of Lrrk2 in order to understand the effect of each LRRK2 mutation. The identification of a large number of presymptomatic LRRK2 mutation carriers provides a unique possibility for future studies on neuroprotection. However, more insight into the basic function of Lrrk2 is needed in order to exploit this potential for translational research.

Loss of LRRK2/PARK8 induces degeneration of dopaminergic neurons in Drosophila

Mutations in LRRK2/PARK8 are linked to autosomal dominant forms of Parkinson’s disease, but the pathogenic mechanism of LRRK2-associated Parkinson’s disease is not fully understood. Moreover, in vivo functions of LRRK2 have not been addressed so far. Thus, we generated and characterized transgenic animals and loss-of-function mutants for LRRK, a sole Drosophila orthologue of human LRRK2. While transgenic expression of pathogenic mutant and wild type LRRK did not show any significant defects, LRRK loss-of-function mutants exhibited severely impaired locomotive activity. Moreover, dopaminergic neurons in LRRK mutants showed a severe reduction in tyrosine hydroxylase immunostaining and shrunken morphology, implicating their degeneration in the mutants. Collectively, our findings unprecedentedly show in vivo that LRRK2 is critical for the integrity of dopaminergic neurons and intact locomotive activity in Drosophila.