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Impaired β-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations
- 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.
- Subjects :
- Male
Aging
Neuronal Ceroid Lipofuscinosis
Neurodegenerative
Inbred C57BL
lcsh:RC346-429
Pathogenesis
Mice
0302 clinical medicine
Progranulins
Loss of Function Mutation
80 and over
2.1 Biological and endogenous factors
Aetiology
Alzheimer's Disease Related Dementias (ADRD)
Glycosphingolipid
Aged, 80 and over
Mice, Knockout
Neurons
0303 health sciences
Neurodegeneration
Lysosome
Frontotemporal Dementia (FTD)
medicine.anatomical_structure
Frontotemporal Dementia
Neurological
Glucosylceramidase
Female
Haploinsufficiency
Frontotemporal dementia
medicine.medical_specialty
Progranulin
Knockout
Clinical Sciences
Prefrontal Cortex
and over
Neuropathology
Pathology and Forensic Medicine
Lipofuscin
03 medical and health sciences
Cellular and Molecular Neuroscience
Rare Diseases
Internal medicine
mental disorders
Acquired Cognitive Impairment
medicine
Animals
Humans
lcsh:Neurology. Diseases of the nervous system
030304 developmental biology
Aged
business.industry
Research
Neurosciences
Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)
medicine.disease
β-Glucocerebrosidase
Brain Disorders
Mice, Inbred C57BL
Endocrinology
HEK293 Cells
Dementia
Neuronal ceroid lipofuscinosis
Biochemistry and Cell Biology
Neurology (clinical)
business
beta-Glucocerebrosidase
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 20515960
- Volume :
- 7
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Acta Neuropathologica Communications
- Accession number :
- edsair.doi.dedup.....07ccda55fe93e4f7a531f674858b170c