Progranulin deficiency leads to reduced glucocerebrosidase activity

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

doi:10.1371/journal.pone.0212382

Cited by 62 publications

(42 citation statements)

References 66 publications

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“…These GCase deficits may be caused by impaired GCase processing due to progranulin insufficiency. This work adds to prior reports that progranulin interacts with GCase [29, 30], and recent reports of reduced GCase activity in brains from Grn −/− mice [72] and iPSC-derived neurons from GRN mutation carriers [65], further supporting the requirement of progranulin for normal GCase activity in the brain.…”

Section: Discussionsupporting

confidence: 82%

Impaired β-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations

Arrant

Roth

Boyle

et al. 2019

acta neuropathol commun

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Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia. Most pathogenic GRN mutations result in progranulin haploinsufficiency, which is thought to cause frontotemporal dementia in GRN mutation carriers. Progranulin haploinsufficiency may drive frontotemporal dementia pathogenesis by disrupting lysosomal function, as patients with GRN mutations on both alleles develop the lysosomal storage disorder neuronal ceroid lipofuscinosis, and frontotemporal dementia patients with GRN mutations (FTD-GRN) also accumulate lipofuscin. The specific lysosomal deficits caused by progranulin insufficiency remain unclear, but emerging data indicate that progranulin insufficiency may impair lysosomal sphingolipid-metabolizing enzymes. We investigated the effects of progranulin insufficiency on sphingolipid-metabolizing enzymes in the inferior frontal gyrus of FTD-GRN patients using fluorogenic activity assays, biochemical profiling of enzyme levels and posttranslational modifications, and quantitative neuropathology. Of the enzymes studied, only β-glucocerebrosidase exhibited impairment in FTD-GRN patients. Brains from FTD-GRN patients had lower activity than controls, which was associated with lower levels of mature β-glucocerebrosidase protein and accumulation of insoluble, incompletely glycosylated β-glucocerebrosidase. Immunostaining revealed loss of neuronal β-glucocerebrosidase in FTD-GRN patients. To investigate the effects of progranulin insufficiency on β-glucocerebrosidase outside of the context of neurodegeneration, we investigated β-glucocerebrosidase activity in progranulin-insufficient mice. Brains from Grn−/− mice had lower β-glucocerebrosidase activity than wild-type littermates, which was corrected by AAV-progranulin gene therapy. These data show that progranulin insufficiency impairs β-glucocerebrosidase activity in the brain. This effect is strongest in neurons and may be caused by impaired β-glucocerebrosidase processing.

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Section: Discussionsupporting

confidence: 82%

Impaired β-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations

Arrant

Roth

Boyle

et al. 2019

acta neuropathol commun

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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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“…Progranulin is necessary for maintaining lysosomal function, as shown by the development of NCL in homozygous GRN mutation carriers (5)(6)(7). While the function of progranulin in lysosomes is not well understood, progranulin facilitates the activity of several lysosomal enzymes (22,(46)(47)(48)(49)(50)(51)(52)(53), including the critical protease cathepsin D (22,46,47,52,53).…”

Section: Introductionmentioning

confidence: 99%

Delivering progranulin to neuronal lysosomes protects against excitotoxicity

Davis¹,

Roth²,

Aljabi³

et al. 2021

Journal of Biological Chemistry

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Progranulin deficiency leads to reduced glucocerebrosidase activity

Cited by 62 publications

References 66 publications

Impaired β-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations

Impaired β-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations

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

Delivering progranulin to neuronal lysosomes protects against excitotoxicity

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