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 rescueGRNhaploinsufficiency 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 withGRNloss-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.

Suberoylanilide Hydroxamic Acid (Vorinostat) Up-regulates Progranulin Transcription

“…Recently, Capell et al (11) reported that an inhibitor of vacuolar ATPase, bafilomycin A 1 , and the alkalizing drugs chloroquine, bepridil, and amiodarone increased secreted progranulin levels from haploinsufficient primary human lymphoblasts, although only bafilomycin A 1 increased the protein to nearnormal levels. Bafilomycin exerts its effect through a post-transcriptional mechanism, suggesting a potential synergistic application with SAHA for FTD prevention depending on toxicity and tolerated dose.…”

“…Therefore, increasing progranulin expression from the wild-type allele may prevent or slow down disease progression. Following this rationale, Capell et al (11) recently reported that alkalizing drugs and vacuolar ATPase inhibitors increase progranulin expression through a post-transcriptional mechanism.…”

Progranulin: A Proteolytically Processed Protein at the Crossroads of Inflammation and Neurodegeneration

“…Serum progranulin levels are lower in mutation carriers and patients (lower than ϳ60 ng/ml) than in controls (higher than ϳ125 ng/ml) (26,27). Based on the rationale that FTLD-TDP with GRN mutations is caused by haploinsufficiency of progranulin, small molecule enhancers of progranulin expression have been pursued as potential treatments (28,29). …”

Frontotemporal Lobar Degeneration

“…Former classifications used different numbers: type I by Mackenzie et al and type 3 by Sampathu and co-workers (Mackenzie, Baker et al 2006;Sampathu, Neumann et al 2006). Mutations in PGRN may also present clinically also with symptoms of parkinsonism (FTDP-17) (Benussi, Binetti et al 2008;Boeve and Hutton 2008;Ghetti, Spina et al 2008;Gabryelewicz, Masellis et al 2010;Di Fabio, Tessa et al 2010 concentration of progranulin intra-and extracellularly in an animal model (Capell, Liebscher et al 2011). This may prevent progranulin-mediated neurodegeneration and may be a feasible therapeutic option.…”