title: A transgenic mouse model of the ubiquitin/proteasome system.
abstract: Impairment of the ubiquitin/proteasome system has been proposed to play a role in neurodegenerative disorders such as Alzheimer and Parkinson diseases. Although recent studies confirmed that some disease-related proteins block proteasomal degradation, and despite the existence of excellent animal models of both diseases, in vivo data about the system are lacking. We have developed a model for in vivo analysis of the ubiquitin/proteasome system by generating mouse strains transgenic for a green fluorescent protein (GFP) reporter carrying a constitutively active degradation signal. Administration of proteasome inhibitors to the transgenic animals resulted in a substantial accumulation of GFP in multiple tissues, confirming the in vivo functionality of the reporter. Moreover, accumulation of the reporter was induced in primary neurons by UBB+1, an aberrant ubiquitin found in Alzheimer disease. These transgenic animals provide a tool for monitoring the status of the ubiquitin/proteasome system in physiologic or pathologic conditions.
authors.affiliation: Microbiology and Tumor Biology Center, Karolinska Institutet, Box 280, S-171 77 Stockholm, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Lindsten
authors.forename: Victoria
authors.initials: V
authors.lastname: Menéndez-Benito
authors.forename: Maria G
authors.initials: MG
authors.lastname: Masucci
authors.forename: Nico P
authors.initials: NP
authors.lastname: Dantuma
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice / Q000235:genetics; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence / Q000379:methods; D023421:Models, Animal; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D009928:Organ Specificity; D010300:Parkinson Disease / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014018:Tissue Distribution; D025801:Ubiquitin / Q000187:drug effects / Q000378:metabolism*
chemical_list: D001897:Boronic Acids; D007976:Leupeptins; C423917:MG 262; D009097:Multienzyme Complexes; D009842:Oligopeptides; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C078846:epoxomicin