################################################################################## # Document Properties Section SET DOCUMENT Name = "Document name" SET DOCUMENT Description = "Document description" SET DOCUMENT Version = "1.0" SET DOCUMENT Copyright = "Copyright (c) 2012, akodamullil. All Rights Reserved." SET DOCUMENT Authors = "akodamullil" SET DOCUMENT Licenses = "Document license" SET DOCUMENT ContactInfo = "your@email.com" ################################################################################## # Definitions Section DEFINE NAMESPACE PFR AS URL "http://resource.belframework.org/belframework/1.0/namespace/selventa-named-rat-protein-families.belns" DEFINE NAMESPACE MGI AS URL "http://resource.belframework.org/belframework/1.0/namespace/mgi-approved-symbols.belns" DEFINE NAMESPACE PFM AS URL "http://resource.belframework.org/belframework/1.0/namespace/selventa-named-mouse-protein-families.belns" DEFINE NAMESPACE MESHPP AS URL "http://resource.belframework.org/belframework/1.0/namespace/mesh-biological-processes.belns" DEFINE NAMESPACE MESHCL AS URL "http://resource.belframework.org/belframework/1.0/namespace/mesh-cellular-locations.belns" DEFINE NAMESPACE NCH AS URL "http://resource.belframework.org/belframework/1.0/namespace/selventa-named-human-complexes.belns" DEFINE NAMESPACE CHEBI AS URL "http://resource.belframework.org/belframework/1.0/namespace/chebi-names.belns" DEFINE NAMESPACE NCR AS URL "http://resource.belframework.org/belframework/1.0/namespace/selventa-named-rat-complexes.belns" DEFINE NAMESPACE HGNC AS URL "http://resource.belframework.org/belframework/1.0/namespace/hgnc-approved-symbols.belns" DEFINE NAMESPACE SPAC AS URL "http://resource.belframework.org/belframework/1.0/namespace/swissprot-accession-numbers.belns" DEFINE NAMESPACE PFH AS URL "http://resource.belframework.org/belframework/1.0/namespace/selventa-named-human-protein-families.belns" DEFINE NAMESPACE NCM AS URL "http://resource.belframework.org/belframework/1.0/namespace/selventa-named-mouse-complexes.belns" DEFINE NAMESPACE CHEBIID AS URL "http://resource.belframework.org/belframework/1.0/namespace/chebi-ids.belns" DEFINE NAMESPACE RGD AS URL "http://resource.belframework.org/belframework/1.0/namespace/rgd-approved-symbols.belns" DEFINE NAMESPACE MESHD AS URL "http://resource.belframework.org/belframework/1.0/namespace/mesh-diseases.belns" DEFINE NAMESPACE GO AS URL "http://resource.belframework.org/belframework/1.0/namespace/go-biological-processes-names.belns" DEFINE NAMESPACE SCHEM AS URL "http://resource.belframework.org/belframework/1.0/namespace/selventa-legacy-chemical-names.belns" DEFINE NAMESPACE EGID AS URL "http://resource.belframework.org/belframework/1.0/namespace/entrez-gene-ids-hmr.belns" DEFINE NAMESPACE GOCCACC AS URL "http://resource.belframework.org/belframework/1.0/namespace/go-cellular-component-accession-numbers.belns" DEFINE NAMESPACE GOCCTERM AS URL "http://resource.belframework.org/belframework/1.0/namespace/go-cellular-component-terms.belns" DEFINE NAMESPACE HGU95AV2 AS URL "http://resource.belframework.org/belframework/1.0/namespace/affy-hg-u95av2.belns" DEFINE NAMESPACE HGU133P2 AS URL "http://resource.belframework.org/belframework/1.0/namespace/affy-hg-u133-plus2.belns" DEFINE NAMESPACE HGU133AB AS URL "http://resource.belframework.org/belframework/1.0/namespace/affy-hg-u133ab.belns" DEFINE NAMESPACE MGU74ABC AS URL "http://resource.belframework.org/belframework/1.0/namespace/affy-mg-u74abc.belns" DEFINE NAMESPACE MG430AB AS URL "http://resource.belframework.org/belframework/1.0/namespace/affy-moe430ab.belns" DEFINE NAMESPACE MG4302 AS URL "http://resource.belframework.org/belframework/1.0/namespace/affy-mouse430-2.belns" DEFINE NAMESPACE MG430A2 AS URL "http://resource.belframework.org/belframework/1.0/namespace/affy-mouse430a-2.belns" DEFINE NAMESPACE RG230AB AS URL "http://resource.belframework.org/belframework/1.0/namespace/affy-rae230ab-2.belns" DEFINE NAMESPACE RG2302 AS URL "http://resource.belframework.org/belframework/1.0/namespace/affy-rat230-2.belns" DEFINE ANNOTATION HemicAndImmuneSystem AS URL "http://resource.belframework.org/belframework/1.0/annotation/mesh-hemic-and-immune-system.belanno" DEFINE ANNOTATION UrogenitalSystem AS URL "http://resource.belframework.org/belframework/1.0/annotation/mesh-urogenital-system.belanno" DEFINE ANNOTATION FluidAndSecretion AS URL "http://resource.belframework.org/belframework/1.0/annotation/mesh-fluid-and-secretion.belanno" DEFINE ANNOTATION CellStructure AS URL "http://resource.belframework.org/belframework/1.0/annotation/mesh-cell-structure.belanno" DEFINE ANNOTATION CellLine AS URL "http://resource.belframework.org/belframework/1.0/annotation/atcc-cell-line.belanno" DEFINE ANNOTATION TextLocation AS LIST {"Abstract","Results","Legend","Review"} DEFINE ANNOTATION IntegumentarySystem AS URL "http://resource.belframework.org/belframework/1.0/annotation/mesh-integumentary-system.belanno" DEFINE ANNOTATION DigestiveSystem AS URL "http://resource.belframework.org/belframework/1.0/annotation/mesh-digestive-system.belanno" DEFINE ANNOTATION MuskuloskeletalSystem AS URL "http://resource.belframework.org/belframework/1.0/annotation/mesh-musculoskeletal-system.belanno" DEFINE ANNOTATION Tissue AS URL "http://resource.belframework.org/belframework/1.0/annotation/mesh-tissue.belanno" DEFINE ANNOTATION BodyRegion AS URL "http://resource.belframework.org/belframework/1.0/annotation/mesh-body-region.belanno" DEFINE ANNOTATION Cell AS URL "http://resource.belframework.org/belframework/1.0/annotation/mesh-cell.belanno" DEFINE ANNOTATION NervousSystem AS URL "http://resource.belframework.org/belframework/1.0/annotation/mesh-nervous-system.belanno" DEFINE ANNOTATION SenseOrgan AS URL "http://resource.belframework.org/belframework/1.0/annotation/mesh-sense-organ.belanno" DEFINE ANNOTATION Disease AS URL "http://resource.belframework.org/belframework/1.0/annotation/mesh-disease.belanno" DEFINE ANNOTATION RespiratorySystem AS URL "http://resource.belframework.org/belframework/1.0/annotation/mesh-respiratory-system.belanno" DEFINE ANNOTATION Species AS URL "http://resource.belframework.org/belframework/1.0/annotation/species-taxonomy-id.belanno" DEFINE ANNOTATION CardiovascularSystem AS URL "http://resource.belframework.org/belframework/1.0/annotation/mesh-cardiovascular-system.belanno" DEFINE ANNOTATION EndocrineSystem AS URL "http://resource.belframework.org/belframework/1.0/annotation/mesh-endocrine-system.belanno" ################################################################################## # Statements Section SET STATEMENT_GROUP = "Group 1" # Add statements below this comment ######################## SET Citation={"PubMed","Neurology. 2008 Sep 23;71(13):1021-6. doi: 10.1212/01.wnl.0000326575.20829.45.","18809839"} SET Evidence ="Mutations in PARK8 (LRRK2) are associated with autosomal dominant parkinsonism and Parkinson disease \ (PD). The mean UPSIT score in G2019S parkinsonian carriers was lower than that in healthy controls (p < 0.001) and \ similar to that found in patients with PD (p > 0.999)." p(HGNC:LRRK2,sub(G,2019,S)) -> path(MESHD:"Parkinson Disease") ######################## SET Citation={"PubMed","J Biomed Sci. 2008 Sep;15(5):661-7. doi: 10.1007/s11373-008-9260-0. Epub 2008 Jun 4.","18523869"} SET Evidence =" The clinical phenotypes and [(18)F]-dopa PET findings for subjects with R1441H or G2385R resembled \ those of patients with idiopathic PD. Pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) cause \ autosomal-dominant familial Parkinson's disease (PD)." p(HGNC:LRRK2,sub(R,1441,H)) -> path(MESHD:"Parkinson Disease") p(HGNC:LRRK2,sub(G,2385,R)) -> path(MESHD:"Parkinson Disease") ######################## SET Citation={"PubMed","Mov Disord. 2006 Aug;21(8):1144-7.","16671078"} SET Evidence ="We conclude that in these patients carrying the LRRK2 Gly2019Ser mutation, the neurodegenerative \ process results in a pattern of nigrostriatal dopaminergic dysfunction similar to that observed in IPD." p(HGNC:LRRK2,sub(G,2019,S)) -> path(MESHD:"Parkinson Disease") ######################## SET Citation={"PubMed","Exp Cell Res. 2007 Oct 1;313(16):3658-70. Epub 2007 Jul 19.","17706965"} SET Evidence ="The PD-associated mutation, R1441C, located within the Roc domain, leads to an increase in LRRK2 \ kinase activity and a decrease in the rate of GTP hydrolysis, compared to the wild-type protein, in an in vitro \ assay. This finding suggests that the R1441C mutation may help stabilize an activated state of LRRK2. \ Additionally, LRRK2-mediated phosphorylation is stimulated upon binding of non-hydrolyzable GTP analogs, \ suggesting that LRRK2 is an MAPKKK-activated intramolecularly by its own GTPase. Since GTPases and MAPKKKs \ are upstream regulators of multiple signal transduction cascades, LRRK2 may play a central role in integrating \ pathways involved in neuronal cell signaling and the pathogenesis of PD." p(HGNC:LRRK2,sub(R,1441,C)) -> kin(p(HGNC:LRRK2)) p(HGNC:LRRK2,sub(R,1441,C)) -| bp(GO:"cell-cell signaling") p(HGNC:LRRK2,sub(R,1441,C)) -> path(MESHD:"Parkinson Disease") ######################## SET Citation={"PubMed","Hum Mol Genet. 2006 Jan 15;15(2):223-32. Epub 2005 Dec 1.","16321986"} SET Evidence ="The disease-associated I2020T mutant shows a significant increase in autophosphorylation of \ approximately 40% in comparison to wild-type protein in vitro. This suggests that the pathology of PD \ caused by the I2020T mutation is associated with an increase rather than a loss in LRRK2 kinase activity." p(HGNC:LRRK2,sub(I,2020,T)) -> kin(p(HGNC:LRRK2)) kin(p(HGNC:LRRK2)) -> p(HGNC:LRRK2,pmod(P)) ######################## SET Citation={"PubMed","J Neurochem. 2009 May;109(4):959-68. doi: 10.1111/j.1471-4159.2009.06024.x. Epub 2009 Mar 3.","19302196"} SET Evidence =" Therefore, we addressed the question if LRRK2 exhibits MAPKKK activity by systematically \ testing MAPKKs as candidate substrates, in vitro. We demonstrate that LRRK2 variants phosphorylate \ mitogen-activated protein kinase kinases (MAPKK), including MKK3 -4, -6 and -7. MKKs act upstream of \ the MAPK p38 and JNK mediating oxidative cell stress, neurotoxicity and apoptosis. The disease-associated \ LRRK2 G2019S and I2020T mutations show an increased phosphotransferase activity towards MKKs correlating \ with the activity shown for its autophosphorylation. Our findings present evidence of a new class of \ molecular targets for mutant LRRK2 that link to neurotoxicity, cellular stress, cytoskeletal dynamics \ and vesicular transport." p(HGNC:LRRK2,sub(G,2019,S)) -> kin(p(HGNC:LRRK2)) p(HGNC:LRRK2,sub(I,2020,T)) -> kin(p(HGNC:LRRK2)) kin(p(HGNC:LRRK2)) -> p(HGNC:MAP2K3,pmod(P)) kin(p(HGNC:LRRK2)) -> p(HGNC:MAP2K4,pmod(P)) kin(p(HGNC:LRRK2)) -> p(HGNC:MAP2K6,pmod(P)) kin(p(HGNC:LRRK2)) -> p(HGNC:MAP2K7,pmod(P)) ######################## SET Citation={"PubMed","Hum Genet. 2007 Feb;120(6):857-63. Epub 2006 Sep 30.","17019612"} SET Evidence =" In transfection studies, we demonstrated that both the wild type and Gly2385Arg variant \ LRRK2 protein localize to the cytoplasm and form aggregates. However, under condition of oxidative \ stress, the Gly2385Arg variant was more toxic and associated with a higher rate of apoptosis. Our \ study lends support to the contention that the Gly2385Arg is a common risk factor for PD in the \ Chinese population. Our bioinformatics and in-vitro studies also suggest that the Gly2385Arg variant \ is biologically relevant and it might act through pro-apoptotic mechanisms." p(HGNC:LRRK2,sub(G,2019,R)) -> path(MESHD:"Parkinson Disease") p(HGNC:LRRK2,sub(G,2019,R)) -> bp(GO:apoptosis) ######################## SET Citation={"PubMed","J Neurosci. 2008 Mar 26;28(13):3384-91. doi: 10.1523/JNEUROSCI.0185-08.2008.","18367605"} SET Evidence ="The substitution of serine for glycine at position 2019 (G2019S) in the kinase \ domain of LRRK2 represents the most prevalent genetic mutation in both familial and apparently \ sporadic cases of PD. Because mutations in LRRK2 are likely associated with a toxic gain of function, \ destabilization of LRRK2 may be a novel way to limit its detrimental effects. Here we show that LRRK2 \ forms a complex with heat shock protein 90 (Hsp90) in vivo and that inhibition of Hsp90 disrupts the \ association of Hsp90 with LRRK2 and leads to proteasomal degradation of LRRK2. Hsp90 inhibitors may therefore \ limit the mutant LRRK2-elicited toxicity to neurons. As a proof of principle, we show that Hsp90 inhibitors \ rescue the axon growth retardation caused by overexpression of the LRRK2 G2019S mutation in neurons. Therefore, \ inhibition of LRRK2 kinase activity can be achieved by blocking Hsp90-mediated chaperone activity and Hsp90 \ inhibitors may serve as potential anti-PD drugs." p(HGNC:LRRK2,sub(G,2019,S)) -> path(MESHD:"Parkinson Disease") complex(p(HGNC:HSP90AA1),p(HGNC:LRRK2)) -| bp(GO:axonogenesis) ######################## SET Citation={"PubMed","Hum Mol Genet. 2007 Sep 1;16(17):2031-9. Epub 2007 Jun 20.","17584768"} SET Evidence ="Pathogenic mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant \ and certain cases of sporadic Parkinson's disease (PD). The G2019S substitution in LRRK2 is the most common \ genetic determinant of PD identified so far, and maps to a specific region of the kinase domain called the \ activation segment. The prominent pathogenic G2019S mutation in LRRK2 results in altered autophosphorylation, \ and increased autophosphorylation and substrate phosphorylation, through a process that seems to involve \ reorganization of the activation segment. Our results suggest a molecular mechanistic explanation for how \ the G2019S mutation enhances the catalytic activity of LRRK2, thereby leading to pathogenicity. These \ findings have important implications for therapeutic strategies in PD." p(HGNC:LRRK2,sub(G,2019,S)) -> path(MESHD:"Parkinson Disease") p(HGNC:LRRK2,sub(G,2019,S)) -> (kin(p(HGNC:LRRK2)) -> p(HGNC:LRRK2,pmod(P))) ######################## SET Citation={"PubMed","J Neurol Sci. 2008 Jul 15;270(1-2):94-8. doi: 10.1016/j.jns.2008.02.010. Epub 2008 Mar 19.","18353371"} SET Evidence ="In this brain bank-based series, LRRK2 G2019S mutation occurred in patients with parkinsonism \ associated with either typical brainstem LB pathology or non-specific nigral degeneration." p(HGNC:LRRK2,sub(G,2019,S)) -> path(MESHD:"Parkinson Disease") ######################## SET Citation={"PubMed","J Neurochem. 2009 Sep;110(5):1514-22. doi: 10.1111/j.1471-4159.2009.06235.x. Epub 2009 Jun 22.","19545277"} SET Evidence ="These findings suggest that LRRK2(G2019S)-induced neurodegeneration in Parkinsonian brains \ may be partly mediated by increased phosphorylation of tubulin-beta and constraining of microtubule dynamics." p(HGNC:LRRK2,sub(G,2019,S)) -> path(MESHD:"Parkinson Disease") p(HGNC:LRRK2,sub(G,2019,S)) -> p(HGNC:TUBB,pmod(P)) UNSET STATEMENT_GROUP

Jankovic, J. J. T. E., & Tolosa. (2007). Parkinson's disease and movement disorders. E. Tolosa (Ed.). Lippincott Williams & Wilkins.

LRRK2

Parkinsonism caused by mutations in the gene for Leucine-Rich Repeat Kinase 2