title: Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: a novel therapeutic lead to treat frontotemporal dementia.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Pharmacology, Emory University, School of Medicine, 1510 Clifton Rd, Atlanta, GA, 30322, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Holler
authors.affiliation: Department of Pharmacology, Emory University, School of Medicine, 1510 Clifton Rd, Atlanta, GA, 30322, USA.
authors.forename: Georgia
authors.initials: G
authors.lastname: Taylor
authors.affiliation: Laboratory of Translational Cell Biology, Emory University, School of Medicine, Atlanta, GA, 30322, USA.|Department of Cell Biology, Emory University, School of Medicine, Atlanta, GA, 30322, USA.|Coulter Department of Biomedical Engineering, Georgia Institute of Technology, 313 Ferst Drive, Atlanta, GA, 30332, USA.
authors.forename: Zachary T
authors.initials: ZT
authors.lastname: McEachin
authors.affiliation: Department of Pharmacology, Emory University, School of Medicine, 1510 Clifton Rd, Atlanta, GA, 30322, USA.
authors.forename: Qiudong
authors.initials: Q
authors.lastname: Deng
authors.affiliation: Department of Pharmacology, Emory University, School of Medicine, 1510 Clifton Rd, Atlanta, GA, 30322, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Watkins
authors.affiliation: Department of Pharmacology, Emory University, School of Medicine, 1510 Clifton Rd, Atlanta, GA, 30322, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Hudson
authors.affiliation: Laboratory of Translational Cell Biology, Emory University, School of Medicine, Atlanta, GA, 30322, USA.|Department of Cell Biology, Emory University, School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Easley
authors.affiliation: Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta, GA, 30322, USA.|Department of Neurology, Emory University, School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Hu
authors.affiliation: Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta, GA, 30322, USA.|Department of Neurology, Emory University, School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Chadwick M
authors.initials: CM
authors.lastname: Hales
authors.affiliation: Laboratory of Translational Cell Biology, Emory University, School of Medicine, Atlanta, GA, 30322, USA.|Department of Cell Biology, Emory University, School of Medicine, Atlanta, GA, 30322, USA.|Coulter Department of Biomedical Engineering, Georgia Institute of Technology, 313 Ferst Drive, Atlanta, GA, 30332, USA.|Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Rossoll
authors.affiliation: Laboratory of Translational Cell Biology, Emory University, School of Medicine, Atlanta, GA, 30322, USA.|Department of Cell Biology, Emory University, School of Medicine, Atlanta, GA, 30322, USA.|Coulter Department of Biomedical Engineering, Georgia Institute of Technology, 313 Ferst Drive, Atlanta, GA, 30332, USA.|Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta, GA, 30322, USA.|Department of Neurology, Emory University, School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Bassell
authors.affiliation: Department of Pharmacology, Emory University, School of Medicine, 1510 Clifton Rd, Atlanta, GA, 30322, USA. tkukar@emory.edu.|Center for Neurodegenerative Disease, Emory University, School of Medicine, Atlanta, GA, 30322, USA. tkukar@emory.edu.|Department of Neurology, Emory University, School of Medicine, Atlanta, GA, 30322, USA. tkukar@emory.edu.
authors.forename: Thomas
authors.identifier: 0000-0002-3750-6262
authors.initials: T
authors.lastname: Kukar
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D015153:Blotting, Western; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D057180:Frontotemporal Dementia; D015870:Gene Expression / Q000187:drug effects*; D000077155:Granulins; D057895:Haploinsufficiency; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000077153:Progranulins; D060888:Real-Time Polymerase Chain Reaction; D014199:Trehalose / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: C492314:GRN protein, human; D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D000077153:Progranulins; D014199:Trehalose
keywords: Alzheimer’s disease; Autophagy; Frontotemporal dementia; Frontotemporal lobar degeneration; Lysosome; Lysosome storage disease; Neurodegeneration; Neuronal ceroid lipofuscinosis; Parkinson’s disease; Progranulin; TDP-43; TFEB; Trehalose; Ubiquitin