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Author Notes:

Correspondence should be addressed to Thomas Kukar, Ph.D., Department of Pharmacology, Emory University, 1510 Clifton Road, Suite 5123, Atlanta, GA 30322, E-mail: thomas.kukar@emory.edu.

Author contributions: C.J.H. and T.K. designed research; C.J.H., G.T., Q.D., and T.K. performed research; C.J.H., G.T., Q.D., and T.K. analyzed data; C.J.H. and T.K. wrote the paper.

We thank Dr. Fengua Hu for sharing the mCherry-PGRN construct, Dr. Rosa Rademakers and Dr. Alexandra M. Nicholson for sharing TMEM106B constructs, Dr. Laura Reinholdt at The Jackson Laboratory for providing PGRN KO MEFs, Dr. Marla Gearing for providing postmortem brain tissue, Dr. Chadwick Hales for providing human fibroblasts, and Dr. Craig Heilman for making the Emory PGRN (4C1) antibody.

We also thank custom cloning performed by Dr. Oskar Laur within the Emory Integrated Genomics Core (EIGC).

The authors declare competing financial interests. A patent related to this work entitled “Methods to treat neurodegeneration with granulins” has been filed.


Research Funding:

This work was supported by National Institutes of Health (NIH) Grants R00AG032362 and R01NS093362, a New Vision Award (Donors Cure Foundation), an Emory University Research Committee grant, the Emory Alzheimer’s Disease Center Pilot Grant P50AG025688, the Alzheimer’s Association New Investigator Research grant, the Association for Frontotemporal Degeneration, and the Bluefield Project to Cure Frontotemporal Dementia (T.K.).

Q.D. and C.H. were supported by the NIH T32 Training Grant 2T32NS007480.

Additional support was provided by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454.

Research reported in this publication was supported in part by the Neuropathology Core, EICI, and EIPC of the Emory Neuroscience NINDS Core Facilities Grant, 5P30NS055077.


  • Alzheimer's disease
  • Parkinson's disease
  • amyotophic lateral sclerosis
  • autophagy
  • cathepsin L
  • frontotemporal dementia
  • granulins
  • lysosomal storage disease
  • neurodegeneration
  • neuroinflammation
  • neuronal ceroid lipofuscinosis
  • progranulin

Intracellular Proteolysis of Progranulin Generates Stable, Lysosomal Granulins that Are Haploinsufficient in Patients with Frontotemporal Dementia Caused by GRN Mutations.


Journal Title:



Volume 4, Number 4


, Pages ENEURO.0100-17.2017-ENEURO.0100-17.2017

Type of Work:

Article | Final Publisher PDF


Homozygous or heterozygous mutations in the GRN gene, encoding progranulin (PGRN), cause neuronal ceroid lipofuscinosis (NCL) or frontotemporal dementia (FTD), respectively. NCL and FTD are characterized by lysosome dysfunction and neurodegeneration, indicating PGRN is important for lysosome homeostasis in the brain. PGRN is trafficked to the lysosome where its functional role is unknown. PGRN can be cleaved into seven 6-kDa proteins called granulins (GRNs); however, little is known about how GRNs are produced or if levels of GRNs are altered in FTD-GRN mutation carriers. Here, we report the identification and characterization of antibodies that reliably detect several human GRNs by immunoblot and immunocytochemistry. Using these tools, we find that endogenous GRNs are present within multiple cell lines and are constitutively produced. Further, extracellular PGRN is endocytosed and rapidly processed into stable GRNs within lysosomes. Processing of PGRN into GRNs is conserved between humans and mice and is modulated by sortilin expression and mediated by cysteine proteases (i.e. cathpesin L). Induced lysosome dysfunction caused by alkalizing agents or increased expression of transmembrane protein 106B (TMEM106B) inhibit processing of PGRN into GRNs. Finally, we find that multiple GRNs are haploinsufficient in primary fibroblasts and cortical brain tissue from FTD-GRN patients. Taken together, our findings raise the interesting possibility that GRNs carry out critical lysosomal functions and that loss of GRNs should be explored as an initiating factor in lysosomal dysfunction and neurodegeneration caused by GRN mutations.

Copyright information:

© 2017 Holler et al.

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