title: The mouse/human cross-species heterodimer of leucine-rich repeat kinase 2: possible significance in the transgenic model mouse of Parkinson's disease.
abstract: Leucine-rich repeat kinase (LRRK2) is the causal molecule of autosomal dominant Parkinson's disease (PD). We previously reported that intracellular degradation of wild-type (WT) LRRK2 is promoted by formation of heterodimers with the I2020T mutant LRRK2. In the present study, we investigated whether this is also the case for mouse/human cross-species heterodimers, which could be formed in transgenic mice. First, by co-transfection and immunoprecipitation, we identified the cross-species heterodimer of mouse LRRK2 and human LRRK2. Next, we found that the protein level of mouse LRRK2 decreased when co-transfected with human I2020T LRRK2, but not with human WT LRRK2. These results suggested that degradation of mouse LRRK2 was promoted by formation of a cross-species heterodimer with the mutant LRRK2. In I2020T LRRK2-transgenic mice, the lower protein level of brain LRRK2 in comparison with control mice, together with higher expression of the mRNA, suggested that endogenous LRRK2 was degraded by formation of cross-species heterodimers. Our results suggest a new concept of cross-species dimer/oligomer formation in transgenic disease-model mice.
authors.affiliation: Division of Clinical Immunology, Kitasato University Graduate School of Medicine, Kanagawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Miyajima
authors.affiliation: Division of Clinical Immunology, Kitasato University Graduate School of Medicine, Kanagawa, Japan; Research Facility Center for Regenerative Medicine and Cell Design, Kitasato University School of Allied Health Sciences, Kanagawa, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Ohta
authors.affiliation: Division of Clinical Immunology, Kitasato University Graduate School of Medicine, Kanagawa, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kawada
authors.affiliation: Division of Clinical Immunology, Kitasato University Graduate School of Medicine, Kanagawa, Japan; Division of Biochemistry, Kitasato University School of Allied Health Sciences, Kanagawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Maekawa
authors.affiliation: Division of Clinical Immunology, Kitasato University Graduate School of Medicine, Kanagawa, Japan; Research Facility Center for Regenerative Medicine and Cell Design, Kitasato University School of Allied Health Sciences, Kanagawa, Japan. Electronic address: obata@ahs.kitasato-u.ac.jp.
authors.forename: F
authors.initials: F
authors.lastname: Obata
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: Cross-species heterodimer; Intracellular degradation; Leucine-rich repeat kinase 2 (LRRK2); Parkinson’s disease; Transgenic mouse