title: Long-term proteasome dysfunction in the mouse brain by expression of aberrant ubiquitin.
abstract: Many neurodegenerative diseases are characterized by deposits of ubiquitinated and aberrant proteins, suggesting a failure of the ubiquitin-proteasome system (UPS). The aberrant ubiquitin UBB(+1) is one of the ubiquitinated proteins accumulating in tauopathies such as Alzheimer's disease (AD) and polyglutamine diseases such as Huntington's disease. We have generated UBB(+1) transgenic mouse lines with post-natal neuronal expression of UBB(+1), resulting in increased levels of ubiquitinated proteins in the cortex. Moreover, by proteomic analysis, we identified expression changes in proteins involved in energy metabolism or organization of the cytoskeleton. These changes show a striking resemblance to the proteomic profiles of both AD brain and several AD mouse models. Moreover, UBB(+1) transgenic mice show a deficit in contextual memory in both water maze and fear conditioning paradigms. Although UBB(+1) partially inhibits the UPS in the cortex, these mice do not have an overt neurological phenotype. These mouse models do not replicate the full spectrum of AD-related changes, yet provide a tool to understand how the UPS is involved in AD pathological changes and in memory formation.
authors.affiliation: Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands. david.fischer@glpg.com
authors.forename: David F
authors.initials: DF
authors.lastname: Fischer
authors.forename: Renske
authors.initials: R
authors.lastname: van Dijk
authors.forename: Paula
authors.initials: P
authors.lastname: van Tijn
authors.forename: Barbara
authors.initials: B
authors.lastname: Hobo
authors.forename: Marian C
authors.initials: MC
authors.lastname: Verhage
authors.forename: Roel C
authors.initials: RC
authors.lastname: van der Schors
authors.forename: Ka Wan
authors.initials: KW
authors.lastname: Li
authors.forename: Jan
authors.initials: J
authors.lastname: van Minnen
authors.forename: Elly M
authors.initials: EM
authors.lastname: Hol
authors.forename: Fred W
authors.initials: FW
authors.lastname: van Leeuwen