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Progranulin mutations result in impaired processing of prosaposin and reduced glucocerebrosidase activity.

ABSTRACT: Frontotemporal dementia (FTD) is a common neurogenerative disorder characterized by progressive degeneration in the frontal and temporal lobes. Heterozygous mutations in the gene encoding progranulin (PGRN) are a common genetic cause of FTD. Recently, PGRN has emerged as an important regulator of lysosomal function. Here, we examine the impact of PGRN mutations on the processing of full-length prosaposin to individual saposins, which are critical regulators of lysosomal sphingolipid metabolism. Using FTD-PGRN patient-derived cortical neurons differentiated from induced pluripotent stem cells, as well as post-mortem tissue from patients with FTLD-PGRN, we show that PGRN haploinsufficiency results in impaired processing of prosaposin to saposin C, a critical activator of the lysosomal enzyme glucocerebrosidase (GCase). Additionally, we found that PGRN mutant neurons had reduced lysosomal GCase activity, lipid accumulation and increased insoluble α-synuclein relative to isogenic controls. Importantly, reduced GCase activity in PGRN mutant neurons is rescued by treatment with saposin C. Together, these findings suggest that reduced GCase activity due to impaired processing of prosaposin may contribute to pathogenesis of FTD resulting from PGRN mutations.

SUBMITTER: Valdez C

PROVIDER: S-EPMC7104673 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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 ?-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 ?-glucocerebrosidase protein and accumulation of insoluble, incompletely glycosylated ?-glucocerebrosidase. Immunostaining revealed loss of neuronal ?-glucocerebrosidase in FTD-GRN patients. To investigate the effects of progranulin insufficiency on ?-glucocerebrosidase outside of the context of neurodegeneration, we investigated ?-glucocerebrosidase activity in progranulin-insufficient mice. Brains from Grn-/- mice had lower ?-glucocerebrosidase activity than wild-type littermates, which was corrected by AAV-progranulin gene therapy. These data show that progranulin insufficiency impairs ?-glucocerebrosidase activity in the brain. This effect is strongest in neurons and may be caused by impaired ?-glucocerebrosidase processing.

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Progranulin mutations result in impaired processing of prosaposin and reduced glucocerebrosidase activity.

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