title: Kinase activity is required for the toxic effects of mutant LRRK2/dardarin.
abstract: Mutations in the LRRK2 gene, coding for dardarin, cause dominantly inherited Parkinson's disease (PD). Dardarin is a large protein, and mutations are found throughout the gene including the kinase domain. However, it is not clear if kinase activity is important for the damaging effects of pathogenic mutations. In this study, we noted two cellular phenotypes associated with mutant dardarin. First, pathogenic mutations increase the tendency of dardarin to form inclusion bodies. Secondly, neurons and neuronal cell lines undergo cell death after expression of mutant protein. Manipulating activity by replacing the kinase domain with a 'kinase-dead' version blocks inclusion body formation and strongly delays cell death. This predicts that kinase inhibitors will be useful therapeutic agents in patients with LRRK2 mutations and, perhaps, in sporadic PD. We also show that dardarin protein is expressed within human midbrain neurons and that C-terminal epitopes are also found in some Lewy bodies.
authors.affiliation: Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892-3707, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Greggio
authors.forename: Shushant
authors.initials: S
authors.lastname: Jain
authors.forename: Ann
authors.initials: A
authors.lastname: Kingsbury
authors.forename: Rina
authors.initials: R
authors.lastname: Bandopadhyay
authors.forename: Patrick
authors.initials: P
authors.lastname: Lewis
authors.forename: Alice
authors.initials: A
authors.lastname: Kaganovich
authors.forename: Marcel P
authors.initials: MP
authors.lastname: van der Brug
authors.forename: Alexandra
authors.initials: A
authors.lastname: Beilina
authors.forename: Jeff
authors.initials: J
authors.lastname: Blackinton
authors.forename: Kelly Jean
authors.initials: KJ
authors.lastname: Thomas
authors.forename: Rili
authors.initials: R
authors.lastname: Ahmad
authors.forename: David W
authors.initials: DW
authors.lastname: Miller
authors.forename: Sashi
authors.initials: S
authors.lastname: Kesavapany
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.forename: Andrew
authors.initials: A
authors.lastname: Lees
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Harvey
authors.forename: Kirsten
authors.initials: K
authors.lastname: Harvey
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
mesh_terms: D019943:Amino Acid Substitution; D001921:Brain / Q000201:enzymology / Q000473:pathology; D018076:DNA, Complementary / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000235:genetics / Q000473:pathology; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009154:Mutation; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018076:DNA, Complementary; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases