Progranulin deficiency leads to reduced glucocerebrosidase activity

Zhou, Xiaolai; Paushter, Daniel H.; Pagan, Mitchell D.; Kim, Dongsung; Lieberman, Raquel L.; Overkleeft, Herman S.; Sun, Ying; Smolka, Marcus B.; Hu, Fenghua

doi:10.1101/540450

Cited by 16 publications

(22 citation statements)

References 65 publications

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“…Moreover, chemical [ 75 ] or genetic inhibition [ 61 ] of β-glucocerebrosidase (GBA; GCase) activity leading to the accumulation of glucosylceramides also causes increased expression of GPNMB. Progranulin deficiency reduces glucocerebrosidase activity [ 116 , 134 ] suggesting that the accumulation of glucosylceramide or other sphingolipids could be a proximal cause of GPNMB upregulation in the Grn −/− mouse brain, an idea that needs further investigation. Although the precise mechanism that causes GPNMB upregulation in progranulin deficiency is unclear, our data suggest that measurement of GPNMB levels in the CSF could be used to monitor changes in microglial activation and response to therapies in FTD- GRN patients, similar to substrate reduction therapy in lysosome storage disorders [ 71 , 78 , 119 ].…”

Section: Discussionmentioning

confidence: 99%

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

Huang

Modeste

Dammer

et al. 2020

acta neuropathol commun

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Heterozygous, loss-of-function mutations in the granulin gene (GRN) encoding progranulin (PGRN) are a common cause of frontotemporal dementia (FTD). Homozygous GRN mutations cause neuronal ceroid lipofuscinosis-11 (CLN11), a lysosome storage disease. PGRN is a secreted glycoprotein that can be proteolytically cleaved into seven bioactive 6 kDa granulins. However, it is unclear how deficiency of PGRN and granulins causes neurodegeneration. To gain insight into the mechanisms of FTD pathogenesis, we utilized Tandem Mass Tag isobaric labeling mass spectrometry to perform an unbiased quantitative proteomic analysis of whole-brain tissue from wild type (Grn+/+) and Grn knockout (Grn−/−) mice at 3- and 19-months of age. At 3-months lysosomal proteins (i.e. Gns, Scarb2, Hexb) are selectively increased indicating lysosomal dysfunction is an early consequence of PGRN deficiency. Additionally, proteins involved in lipid metabolism (Acly, Apoc3, Asah1, Gpld1, Ppt1, and Naaa) are decreased; suggesting lysosomal degradation of lipids may be impaired in the Grn−/− brain. Systems biology using weighted correlation network analysis (WGCNA) of the Grn−/− brain proteome identified 26 modules of highly co-expressed proteins. Three modules strongly correlated to Grn deficiency and were enriched with lysosomal proteins (Gpnmb, CtsD, CtsZ, and Tpp1) and inflammatory proteins (Lgals3, GFAP, CD44, S100a, and C1qa). We find that lysosomal dysregulation is exacerbated with age in the Grn−/− mouse brain leading to neuroinflammation, synaptic loss, and decreased markers of oligodendrocytes, myelin, and neurons. In particular, GPNMB and LGALS3 (galectin-3) were upregulated by microglia and elevated in FTD-GRN brain samples, indicating common pathogenic pathways are dysregulated in human FTD cases and Grn−/− mice. GPNMB levels were significantly increased in the cerebrospinal fluid of FTD-GRN patients, but not in MAPT or C9orf72 carriers, suggesting GPNMB could be a biomarker specific to FTD-GRN to monitor disease onset, progression, and drug response. Our findings support the idea that insufficiency of PGRN and granulins in humans causes neurodegeneration through lysosomal dysfunction, defects in autophagy, and neuroinflammation, which could be targeted to develop effective therapies.

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Section: Discussionmentioning

confidence: 99%

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

Huang

Modeste

Dammer

et al. 2020

acta neuropathol commun

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“…These granulin peptides have been proposed to possess unique biological activities, in a way similar to the saposin peptides derived from PSAP, which function as activators for enzymes involved in glycosphingolipid degradation (O'Brien & Kishimoto, 1991). In line with this, PGRN and granulin peptides have been shown to regulate the activities of several lysosome enzymes, including cathepsin D (Beel et al, 2017;Butler et al, 2019;Valdez et al, 2017;Zhou et al, 2017a) and glucocerebrosidase (Arrant et al, 2019;Valdez et al, 2019;Zhou et al, 2019).…”

Section: Introductionmentioning

confidence: 89%

Differential regulation of progranulin derived granulin peptides

Zhang

Santos

et al. 2021

Preprint

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Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). PGRN is comprised of 7.5 granulin repeats and is processed into individual granulin peptides in the lysosome. However, very little is known about the levels and regulations of individual granulin peptides due to the lack of specific antibodies. Here we report the generation and characterization of antibodies specific to each granulin peptide. We found that the levels of granulins C, E and F are differentially regulated compared to granulins A and B. Furthermore, we demonstrated that granulin B, C and E are heavily glycosylated and the glycosylation pattern of granulin C varies in different physiological and pathological conditions. Deficiency of lysosomal proteases leads to alterations in the levels of a specific subset of granulins. These data support that the levels of individual granulin peptides are differentially regulated under physiological and pathological conditions and provide novel insights into how granulin peptides function in the lysosome.

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“…Heterozygous mutations in GRN lead to the development of frontotemporal dementia (FTD) and homozygous mutations cause the lysosomal storage disorder, neuronal ceroid lipofuscinosis [35][36][37]. In addition to its role in regulating a multitude of functions including embryogenesis, tumorigenesis, inflammation and wound repair [38,39], recent studies have identified its role in lysosomal function as a chaperone of several lysosomal enzymes such as GCase [40,41], cathepsin D [42] and Hex A [43]. Two modes of regulation of GBA by PGRN have been identified so far.…”

Section: Introductionmentioning

confidence: 99%

Fibroblasts from idiopathic Parkinson’s disease exhibit deficiency of lysosomal glucocerebrosidase activity associated with reduced levels of the trafficking receptor LIMP2

et al. 2021

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Lysosomal dysfunction is a central pathway associated with Parkinson’s disease (PD) pathogenesis. Haploinsufficiency of the lysosomal hydrolase GBA (encoding glucocerebrosidase (GCase)) is one of the largest genetic risk factors for developing PD. Deficiencies in the activity of the GCase enzyme have been observed in human tissues from both genetic (harboring mutations in the GBA gene) and idiopathic forms of the disease. To understand the mechanisms behind the deficits of lysosomal GCase enzyme activity in idiopathic PD, this study utilized a large cohort of fibroblast cells from control subjects and PD patients with and without mutations in the GBA gene (N370S mutation) (control, n = 15; idiopathic PD, n = 31; PD with GBA N370S mutation, n = 6). The current data demonstrates that idiopathic PD fibroblasts devoid of any mutations in the GBA gene also exhibit reduction in lysosomal GCase activity, similar to those with the GBA N370S mutation. This reduced GCase enzyme activity in idiopathic PD cells was accompanied by decreased expression of the GBA trafficking receptor, LIMP2, and increased ER retention of the GBA protein in these cells. Importantly, in idiopathic PD fibroblasts LIMP2 protein levels correlated significantly with GCase activity, which was not the case in control subjects or in genetic PD GBA N370S cells. In conclusion, idiopathic PD fibroblasts have decreased GCase activity primarily driven by altered LIMP2-mediated transport of GBA to lysosome and the reduced GCase activity exhibited by the genetic GBA N370S derived PD fibroblasts occurs through a different mechanism.

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Progranulin deficiency leads to reduced glucocerebrosidase activity

Cited by 16 publications

References 65 publications

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

Differential regulation of progranulin derived granulin peptides

Fibroblasts from idiopathic Parkinson’s disease exhibit deficiency of lysosomal glucocerebrosidase activity associated with reduced levels of the trafficking receptor LIMP2

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