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.

RBR Ubiquitin Ligases: Diversification and Streamlining in Animal Lineages

“…After that, the story reverses, with losses of genes occurring in many lineages and only a few new genes appearing. With the available data, cnidarians and mammals are the only groups that conserve a set of RBR genes that is similar to that of their common ancestors, while other lineages, both protostomates and deuterostomates, have lost several or even most of those genes, a result observed before for other gene families (e.g., Kusserow et al 2005;Marín 2008) This streamlining process was especially extreme in nematodes and dipteran insects. However, after this occurred, some of the organisms with less RBR genes have generated some or even many new genes, duplicates of the few that were still left, thus secondarily increasing the number of RBR genes available.…”

A Novel Approach for Bioinformatics Workflow Discovery

“…In this section, we develop a bioinformatics case study extracted from [26]. In this way, we can illustrate how to use our approach to guide the user in a real web service discovery tasks.…”

“…The steps the user will do manually by himself to build the workflow are [26]: 1) Retrieve the protein sequences of the different domains; 2) Predict the gene structure automatically for the sequences retrieved in Step (1); 3) Align protein sequences to build phylogenetic trees; 4) Build the phylogenetic trees; 5) Analyze the structure of the proteins; In our model the execution process will begin from the last step in the case of "Analyze the structure of proteins", and continue until no more pre-conditions are needed in the process of "Retrieve protein sequences". The experiments we have made until now suggest that the task descriptions are short and simple sentences not complex.…”

Modeling LRRK2 Parkinsonism

“…While invertebrate LRRK2 models have been and will continue to be highly informative, it is important to remember that the LRRK genes are not true orthologues of LRRK2 (Marin, 2008). In addition, physiological limitations include not only the lack of basal ganglia but also their short lifespan, leaving the effects of aging impossible to determine.…”