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

Authors :
Shreya N. Kashyap
Erik D. Roberson
Lea T. Grinberg
Madelyn Q. Hoffmann
William W. Seeley
Andrew E. Arrant
Jonathan R. Roth
Alissa L. Nana
Bruce L. Miller
Eliana Marisa Ramos
Charles F. Murchison
Salvatore Spina
Nicholas R. Boyle
Source :
Acta Neuropathologica Communications, Vol 7, Iss 1, Pp 1-17 (2019), Acta Neuropathologica Communications, Acta neuropathologica communications, vol 7, iss 1
Publication Year :
2019
Publisher :
BMC, 2019.

Abstract

Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia. Most pathogenicGRNmutations result in progranulin haploinsufficiency, which is thought to cause frontotemporal dementia inGRNmutation carriers. Progranulin haploinsufficiency may drive frontotemporal dementia pathogenesis by disrupting lysosomal function, as patients withGRNmutations on both alleles develop the lysosomal storage disorder neuronal ceroid lipofuscinosis, and frontotemporal dementia patients withGRNmutations (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-GRNpatients 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-GRNpatients. Brains from FTD-GRNpatients 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-GRNpatients. 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 fromGrn−/−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.

Details

Language :
English
ISSN :
20515960
Volume :
7
Issue :
1
Database :
OpenAIRE
Journal :
Acta Neuropathologica Communications
Accession number :
edsair.doi.dedup.....07ccda55fe93e4f7a531f674858b170c