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

Christopher J Holler,William J Watkins,Wilfried Rossoll,Georgia Taylor,Gary J Bassell,Chadwick M Hales,Qiudong Deng,Thomas Kukar,William T Hu,Zachary T Mceachin,Charles A Easley,Kathryn Hudson

doi:10.1186/s13024-016-0114-3

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.

Highlights

Progranulin (PGRN) is a secreted growth factor important for neuronal survival and may do so, in part, by regulating lysosome homeostasis
We found that several other compounds that reportedly inhibit mechanistic target of rapamycin (mTOR) increased Granulin gene (GRN) promoter activity (Additional file 1: Table S1), suggesting this signaling pathway may be involved in regulating GRN expression
We found that the transcription factor embryoid bodies (EBs) (TFEB)-Green fluorescent protein (GFP) HeLa cells had a small, but significant increase in both GRN mRNA and PGRN protein compared to wild-type HeLa cells (Fig. 4a–c), indicating that TFEB overexpression modulates PGRN expression via direct or indirect mechanisms

Summary

Introduction

Progranulin (PGRN) is a secreted growth factor important for neuronal survival and may do so, in part, by regulating lysosome homeostasis. 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. FTLD-GRN pathology is characterized by neurodegeneration, neuroinflammation, and intra-neuronal and glial inclusions containing the TAR DNA-binding protein 43 (TDP-43), the autophagy adaptor protein p62/SQSTM1, and ubiquitinated proteins (reviewed in [9]) Accumulation of these proteins suggests that defects in protein removal systems, such as the autophagy-lysosome pathway, may contribute to disease. Complete loss of PGRN causes neuronal ceroid lipofuscinosis (NCL) [11], an early-onset lysosomal storage disease Together, these data indicate that PGRN plays a critical, yet undefined role in lysosome function and homeostasis

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