{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T01:25:08Z","timestamp":1793409908720,"version":"4.5.0"},"reference-count":43,"publisher":"Society for Neuroscience","issue":"5","license":[{"start":{"date-parts":[[2011,8,2]],"date-time":"2011-08-02T00:00:00Z","timestamp":1312243200000},"content-version":"vor","delay-in-days":181,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2011,2,2]]},"abstract":"<jats:p>Numerous loss-of-function mutations in the progranulin (<jats:italic>GRN<\/jats:italic>) gene cause frontotemporal lobar degeneration with ubiquitin and TAR\u2013DNA 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<jats:italic>GRN<\/jats:italic>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<jats:italic>GRN<\/jats:italic>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.<\/jats:p>","DOI":"10.1523\/jneurosci.5757-10.2011","type":"journal-article","created":{"date-parts":[[2011,2,2]],"date-time":"2011-02-02T17:24:17Z","timestamp":1296667457000},"page":"1885-1894","source":"Crossref","is-referenced-by-count":124,"title":["Rescue of Progranulin Deficiency Associated with Frontotemporal Lobar Degeneration by Alkalizing Reagents and Inhibition of Vacuolar 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