Intracellular Proteolysis of Progranulin Generates Stable, Lysosomal Granulins that Are Haploinsufficient in Patients with Frontotemporal Dementia Caused byGRNMutations
Open Access
- 1 July 2017
- journal article
- Published by Society for Neuroscience in eneuro
Abstract
Homozygous or heterozygous mutations in theGRNgene, 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-GRNmutation 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-GRNpatients. 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 byGRNmutations.Funding Information
- HHS | NIH | National Institute on Aging (R00AG032362, P50AG025688)
- HHS | NIH | National Institute of Neurological Disorders and Stroke (R01NS093362, 5P30NS055077, 2T32NS007480)
- Donors Cure Foundation (New Vision Award)
- Alzheimer's Association (New Investigator Research Grant)
- Association for Frontotemporal Degeneration (Pilot grant)
- Bluefiled Project to Cure Frontotemporal Dementia (Investigator grant)
This publication has 84 references indexed in Scilit:
- Mechanisms of Granulin Deficiency: Lessons from Cellular and Animal ModelsMolecular Neurobiology, 2012
- Lysosomal storage disorders: The cellular impact of lysosomal dysfunctionThe Journal of cell biology, 2012
- The role of saposin C in Gaucher diseaseMolecular Genetics and Metabolism, 2012
- Strikingly Different Clinicopathological Phenotypes Determined by Progranulin-Mutation DosageAmerican Journal of Human Genetics, 2012
- Genome-wide Screen Identifies rs646776 near Sortilin as a Regulator of Progranulin Levels in Human PlasmaAmerican Journal of Human Genetics, 2010
- Sortilin-Mediated Endocytosis Determines Levels of the Frontotemporal Dementia Protein, ProgranulinNeuron, 2010
- Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusionsNature Genetics, 2010
- Alzheimer Disease–like Phenotype Associated With the c.154delA Mutation in ProgranulinArchives of Neurology, 2010
- Brain progranulin expression in GRN-associated frontotemporal lobar degenerationActa Neuropathologica, 2009
- Prosaposin deficiency and saposin B deficiency (activator‐deficient metachromatic leukodystrophy): Report on two patients detected by analysis of urinary sphingolipids and carrying novel PSAP gene mutationsAmerican Journal of Medical Genetics Part A, 2009