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          Institute: MPI für Neurobiologie     Collection: Cellular and Systems Neurobiology     Display Documents



  history
ID: 547148.0, MPI für Neurobiologie / Cellular and Systems Neurobiology
Rescue of Progranulin Deficiency Associated with Frontotemporal Lobar Degeneration by Alkalizing Reagents and Inhibition of Vacuolar ATPase
Authors:Capell, A.; Liebscher, S.; Fellerer, K.; Brouwers, N.; Willem, M.; Lammich, S.; Gijselinck, I.; Bittner, T.; Carlson, A. M.; Sasse, F.; Kunze, B.; Steinmetz, H.; Jansen, R.; Dormann, D.; Sleegers, K.; Cruts, M.; Herms, J.; Van Broeckhoven, C.; Haass, C.
Language:English
Date of Publication (YYYY-MM-DD):2011-02-02
Title of Journal:Journal of Neuroscience
Journal Abbrev.:J. Neurosci.
Volume:31
Issue / Number:5
Start Page:1885
End Page:1894
Review Status:Peer-review
Audience:Not Specified
Abstract / Description:Numerous loss-of-function mutations in the progranulin (GRN) gene cause frontotemporal lobar degeneration with ubiquitin and TAR-DNA binding protein 43-positive inclusions by reduced production and secretion of GRN. Consistent with the observation that GRN has neurotrophic properties, pharmacological stimulation of GRN production is a promising approach to rescue GRNhaploinsufficiency and prevent disease progression. We therefore searched for compounds capable of selectively increasing GRN levels. Here, we demonstrate that four independent and highly selective inhibitors of vacuolar ATPase (bafilomycin A1, concanamycin A, archazolid B, and apicularen A) significantly elevate intracellular and secreted GRN. Furthermore, clinically used alkalizing drugs, including chloroquine, bepridil, and amiodarone, similarly stimulate GRN production. Elevation of GRN levels occurs via a translational mechanism independent of lysosomal degradation, autophagy, or endocytosis. Importantly, alkalizing reagents rescue GRN deficiency in organotypic cortical slice cultures from a mouse model for GRN deficiency and in primary cells derived from human patients with GRN loss-of-function mutations. Thus, alkalizing reagents, specifically those already used in humans for other applications, and vacuolar ATPase inhibitors may be therapeutically used to prevent GRN-dependent neurodegeneration.
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Affiliations:MPI für Neurobiologie/Cellular and Systems Neurobiology (Bonhoeffer)
External Affiliations:[Capell, Anja; Liebscher, Sabine; Fellerer, Katrin; Willem, Michael; Lammich, Sven; Carlson, Aaron M.; Dormann, Dorothee; Haass, Christian] Univ Munich, German Ctr Neurodegenerat Dis, D-80336 Munich, Germany.; [Capell, Anja; Fellerer, Katrin; Willem, Michael; Lammich, Sven; Carlson, Aaron M.; Dormann, Dorothee; Haass, Christian] Univ Munich, Adolf Butenandt Inst, D-80336 Munich, Germany.; [Brouwers, Nathalie; Gijselinck, Ilse; Sleegers, Kristel; Cruts, Marc; Van Broeckhoven, Christine] Univ Antwerp VIB, Neurodegenerat Brain Dis Grp, Dept Mol Genet, B-2610 Antwerp, Belgium.; [Brouwers, Nathalie; Gijselinck, Ilse; Sleegers, Kristel; Cruts, Marc; Van Broeckhoven, Christine] Univ Antwerp, Inst Born Bunge, Lab Neurogenet, B-2610 Antwerp, Belgium.; [Bittner, Tobias; Herms, Jochen] Univ Munich, Ctr Neuropathol & Prion Res, D-81377 Munich, Germany.; [Sasse, Florenz; Kunze, Brigitte; Steinmetz, Heinrich; Jansen, Rolf] Helmholtz Ctr Infect Res, D-38124 Braunschweig, Germany.
Identifiers:ISI:000286922100037 [ID No:1]
ISSN:0270-6474 [ID No:2]
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