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

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.

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    Van Deerlin VM, Sleiman PM, Martinez-Lage M, Chen-Plotkin A, Wang LS, Graff-Radford NR, Dickson DW, Rademakers R, Boeve BF, Grossman M, Arnold SE, Mann DM, Pickering-Brown SM, Seelaar H, Heutink P, van Swieten JC, Murrell JR, Ghetti B, Spina S, Grafman J, et al. (2010 ) Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet 42:234–239.

    Not in our library10.1038/ng.536

77. 77.

    Van Kampen JM, Baranowski D, Kay DG (2014 ) Progranulin gene delivery protects dopaminergic neurons in a mouse model of Parkinson's disease. PLoS One 9:e97032.

    Not in our library10.1371/journal.pone.0097032

78. 78.

    Ward ME, Chen R, Huang HY, Ludwig C, Telpoukhovskaia M, Taubes A, Boudin H, Minami SS, Reichert M, Albrecht P, Gelfand JM, Cruz-Herranz A, Cordano C, Alavi MV, Leslie S, Seeley WW, Miller BL, Bigio E, Mesulam MM, Bogyo MS, et al. (2017 ) Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis. Sci Transl Med 9.

    Not in our library10.1126/scitranslmed.aah5642

79. 79.

    Wils H, Kleinberger G, Pereson S, Janssens J, Capell A, Van Dam D, Cuijt I, Joris G, De Deyn PP, Haass C, Van Broeckhoven C, Kumar-Singh S (2012 ) Cellular ageing, increased mortality and FTLD-TDP-associated neuropathology in progranulin knockout mice. J Pathol 228:67–76.

    Not in our library10.1002/path.4043

80. 80.

    Yin F, Dumont M, Banerjee R, Ma Y, Li H, Lin MT, Beal MF, Nathan C, Thomas B, Ding A (2010 ) Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementia. FASEB J 24:4639–4647.

    Not in our library10.1096/fj.10-161471

81. 81.

    Zhang Y, Sloan Steven A, Clarke Laura E, Caneda C, Plaza Colton A, Blumenthal Paul D, Vogel H, Steinberg Gary K, Edwards Michael SB, Li G, Duncan John A, III, Cheshier Samuel H, Shuer Lawrence M, Chang Edward F, Grant Gerald A, Gephart Melanie GH, Barres Ben A (2016 ) Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89:37–53.

    Not in our library10.1016/j.neuron.2015.11.013

82. 82.

    Zheng Y, Brady OA, Meng PS, Mao Y, Hu F (2011 ) C-terminus of progranulin interacts with the beta-propeller region of sortilin to regulate progranulin trafficking. PLoS One 6:e21023.

    Not in our library10.1371/journal.pone.0021023

83. 83.

    Zhou X, Sun L, Bastos de Oliveira F, Qi X, Brown WJ, Smolka MB, Sun Y, Hu F (2015 ) Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin. J Cell Biol 210:991–1002.

    Not in our library10.1083/jcb.201502029

84. 84.

    Zhu J, Nathan C, Jin W, Sim D, Ashcroft GS, Wahl SM, Lacomis L, Erdjument-Bromage H, Tempst P, Wright CD, Ding A (2002 ) Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair. Cell 111:867–878.

    Not in our library10.1016/s0092-8674(02)01141-8

Cited by papers we hold 1

• Prolonged tau clearance and stress vulnerability rescue by pharmacological activation of autophagy in tauopathy neurons · 2020
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