Ancient origin of the Parkinson disease gene LRRK2

Abstract

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.