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

• Type of Material: Article
• Authors: Christopher J. Holler, Emory University; Georgia Taylor, Emory University; Zachary T. McEachin, Emory University; Qiudong Deng, Emory University; William J. Watkins, Emory University; Kathryn Hudson, Emory University; Charles Easley, Emory University; William Hu, Emory University; Chadwick Hales, Emory University; Wilfried Rossoll, Emory University; Gary Bassell, Emory University; Thomas Kukar, Emory University
• Language: English
• Date: 2016-06-24
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2016 The Author(s). The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13024-016-0114-3
• Title of Journal or Parent Work: Molecular Neurodegeneration
• ISSN: 1750-1326
• Volume: 11
• Issue: 1
• Start Page: 46
• End Page: 46
• Grant/Funding Information: C.H. and Q.D. were supported by NIH T32 training grant (2T32NS007480).; New Vision Award (Donors Cure Foundation), the National Institutes of Health grants P30NS069289, R00AG032362, R01NS093362, Emory ADRC pilot project (P50AG025688), the Alzheimer’s Association New Investigator Research Grant, and the Association for Frontotemporal Degeneration (TK).
• Keywords: Neuronal ceroid lipofuscinosis; Ubiquitin; TFEB; Autophagy; Lysosome; Lysosome storage disease; Frontotemporal lobar degeneration; Neurodegeneration; Frontotemporal dementia; TDP-43; Progranulin; Parkinson’s disease; Alzheimer’s disease; Trehalose; Neurology
• Research Categories: Biology, Cell; Health Sciences, Pharmacology; Biology, Neuroscience

Abstract

Background: Progranulin (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. Results: Here, 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. Conclusions: This 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.