Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: a novel therapeutic lead to treat frontotemporal dementia

Abstract

BackgroundProgranulin (PGRN) is a secreted growth factor important for neuronal survival and may do so, in part, by regulating lysosome homeostasis. Mutations in the PGRN gene (GRN) are a common cause of frontotemporal lobar degeneration (FTLD) and lead to disease through PGRN haploinsufficiency. Additionally, complete loss of PGRN in humans leads to neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Importantly, Grn−/− mouse models recapitulate pathogenic lysosomal features of NCL. Further, GRN variants that decrease PGRN expression increase the risk of developing Alzheimer’s disease (AD) and Parkinson’s disease (PD). Together these findings demonstrate that insufficient PGRN predisposes neurons to degeneration. Therefore, compounds that increase PGRN levels are potential therapeutics for multiple neurodegenerative diseases.ResultsHere, we performed a cell-based screen of a library of known autophagy-lysosome modulators and identified multiple novel activators of a human GRN promoter reporter including several common mTOR inhibitors and an mTOR-independent activator of autophagy, trehalose. Secondary cellular screens identified trehalose, a natural disaccharide, as the most promising lead compound because it increased endogenous PGRN in all cell lines tested and has multiple reported neuroprotective properties. Trehalose dose-dependently increased GRN mRNA as well as intracellular and secreted PGRN in both mouse and human cell lines and this effect was independent of the transcription factor EB (TFEB). Moreover, trehalose rescued PGRN deficiency in human fibroblasts and neurons derived from induced pluripotent stem cells (iPSCs) generated from GRN mutation carriers. Finally, oral administration of trehalose to Grn haploinsufficient mice significantly increased PGRN expression in the brain.ConclusionsThis work reports several novel autophagy-lysosome modulators that enhance PGRN expression and identifies trehalose as a promising therapeutic for raising PGRN levels to treat multiple neurodegenerative diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0114-3) contains supplementary material, which is available to authorized users.

Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia

“…For instance, the transcription factor EB (TFEB), a master regulator of autophagy-lysosomal gene expression, is implicated in GRN expression through its specific recognition and binding to E-box consensus sequences ( 5′-CANNTG-3′ ) in the GRN promoter region (Belcastro et al, 2011). Since TFEB overexpression has been shown to be sufficient to enhance GRN mRNA and PGRN protein levels in human cells (Holler et al, 2016), we hypothesized that HDAC inhibitors that affect PGRN expression would have a different effect on TFEB levels than those HDAC inhibitors that do not. Indeed, we observed that the level of this enhancement in TFEB levels correlated with an increase in PGRN in a dose-dependent manner (Figure 8).…”

Progranulin, lysosomal regulation and neurodegenerative disease

“…In addition, stressful stimuli, such as hypoxia, acidosis, hyperosmolarity and inhibition of lysosomal function by artificial alkalinization 52 , seem to increase progranulin production and secretion 72,77,78 , alter its glycosylation 18 and possibly promote its cleavage 12,14,50,51 . Low circulating levels of progranulin in GRN carriers 38 suggest that progranulin expression from the wild-type allele might be a potential therapeutic target.…”

Alagille Syndrome: Genetics and Functional Models

“…These types of studies are currently ongoing for a variety of other diseases. Frontotemporal lobar degeneration occurs via haploinsufficiency of the GRN gene, which encodes the protein progranulin (PGRN), and a recent study to screen a library of small molecules identified a naturally-occurring disaccharide, trehalose, as a molecule capable of increasing endogenous PGRN levels [63]. This group confirmed their findings in both an animal model of the disease and in iPSCs that had innate GRN mutations.…”