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Author Notes:

Correspondence: tkukar@emory.edu

CJH initiated the project; TK, CJH, and GT designed the research.

CJH, GT, ZM, QD, WW, KH performed the research; WTH and CMH contributed patient samples; CAE, WR, and GB provided reagents and equipment; CJH and TK analyzed the data; CJH and TK wrote the paper with input from all authors.

We thank Dr. Shawn Ferguson (Yale University) for providing the TFEB-GFP HeLa cell line.

The authors have declared that they have no competing interests.

Funding bodies played no role in the design of the study, data analysis, interpretation of data, or writing the manuscript.

Ethics approval and consent to participate: Human dermal fibroblasts were collected under protocol 00064365 as approved by the Emory University Institutional Review Board. Informed written consent was obtained for all research subjects. All animal work was conducted with prior Institutional Animal Care and Use Committee (IACUC) approval, and was performed in accordance with Public Health Service guidelines.


Research Funding:

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).

C.H. and Q.D. were supported by NIH T32 training grant (2T32NS007480).


  • 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
  • Neurology

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

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Journal Title:

Molecular Neurodegeneration


Volume 11, Number 1


, Pages 46-46

Type of Work:

Article | Final Publisher PDF


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.

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© 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.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

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