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

ABSTRACT

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