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

• Type of Material: Article
• Authors: Christopher J. Holler, Emory University; Georgia Taylor, Emory University; Qiudong Deng, Emory University; Thomas Kukar, Emory University
• Language: English
• Date: 2017-07
• Publisher: Society for Neuroscience: eNeuro
• Publication Version: Final Published Version
• Copyright Statement: © 2017 Holler et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/ENEURO.0100-17.2017
• Title of Journal or Parent Work: eNeuro
• ISSN: 2373-2822
• Volume: 4
• Issue: 4
• Start Page: ENEURO.0100-17.2017
• End Page: ENEURO.0100-17.2017
• Grant/Funding Information: Additional support was provided by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454.; Q.D. and C.H. were supported by the NIH T32 Training Grant 2T32NS007480.; 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.).; 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.
• Keywords: lysosomal storage disease; Alzheimer's disease; Parkinson's disease; neuronal ceroid lipofuscinosis; autophagy; frontotemporal dementia; neurodegeneration; progranulin; granulins; neuroinflammation; cathepsin L; amyotophic lateral sclerosis
• Research Categories: Health Sciences, General; Biology, Neuroscience

Abstract

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.