title: Rescue of progranulin deficiency associated with frontotemporal lobar degeneration by alkalizing reagents and inhibition of vacuolar ATPase.
abstract: 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 GRN haploinsufficiency 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.
authors.affiliation: German Center for Neurodegenerative Diseases, Ludwig Maximilians University, 80336 Munich, Germany. acapell@med.uni-muenchen.de
authors.forename: Anja
authors.initials: A
authors.lastname: Capell
authors.forename: Sabine
authors.initials: S
authors.lastname: Liebscher
authors.forename: Katrin
authors.initials: K
authors.lastname: Fellerer
authors.forename: Nathalie
authors.initials: N
authors.lastname: Brouwers
authors.forename: Michael
authors.initials: M
authors.lastname: Willem
authors.forename: Sven
authors.initials: S
authors.lastname: Lammich
authors.forename: Ilse
authors.initials: I
authors.lastname: Gijselinck
authors.forename: Tobias
authors.initials: T
authors.lastname: Bittner
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Carlson
authors.forename: Florenz
authors.initials: F
authors.lastname: Sasse
authors.forename: Brigitte
authors.initials: B
authors.lastname: Kunze
authors.forename: Heinrich
authors.initials: H
authors.lastname: Steinmetz
authors.forename: Rolf
authors.initials: R
authors.lastname: Jansen
authors.forename: Dorothee
authors.initials: D
authors.lastname: Dormann
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
authors.forename: Marc
authors.initials: M
authors.lastname: Cruts
authors.forename: Jochen
authors.initials: J
authors.lastname: Herms
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
mesh_terms: D000468:Alkalies / Q000494:pharmacology*; D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000071187:Autophagy-Related Protein 5; D015764:Bepridil / Q000494:pharmacology; D015152:Blotting, Northern; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D002738:Chloroquine / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D057174:Frontotemporal Lobar Degeneration / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000077155:Granulins; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D000077153:Progranulins; D012333:RNA, Messenger / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors*
chemical_list: D000468:Alkalies; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D019086:Bridged Bicyclo Compounds, Heterocyclic; D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D018942:Macrolides; D008869:Microtubule-Associated Proteins; D000077153:Progranulins; D012333:RNA, Messenger; D013844:Thiazoles; C117813:apicularen A; C519728:archazolid B; D015764:Bepridil; C036978:concanamycin A; D002738:Chloroquine; C040929:bafilomycin A1; D025262:Vacuolar Proton-Translocating ATPases; D000638:Amiodarone