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Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis
- Source :
- Science translational medicine, vol 9, iss 385
- Publication Year :
- 2017
- Publisher :
- eScholarship, University of California, 2017.
-
Abstract
- Heterozygous mutations in the GRN gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal dementia (FTD), a neurodegenerative syndrome of older adults. Homozygous GRN mutations, on the other hand, lead to complete PGRN loss and cause neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease usually seen in children. Given that the predominant clinical and pathological features of FTD and NCL are distinct, it is controversial whether the disease mechanisms associated with complete and partial PGRN loss are similar or distinct. We show that PGRN haploinsufficiency leads to NCL-like features in humans, some occurring before dementia onset. Noninvasive retinal imaging revealed preclinical retinal lipofuscinosis in heterozygous GRN mutation carriers. Increased lipofuscinosis and intracellular NCL-like storage material also occurred in postmortem cortex of heterozygous GRN mutation carriers. Lymphoblasts from heterozygous GRN mutation carriers accumulated prominent NCL-like storage material, which could be rescued by normalizing PGRN expression. Fibroblasts from heterozygous GRN mutation carriers showed impaired lysosomal protease activity. Our findings indicate that progranulin haploinsufficiency caused accumulation of NCL-like storage material and early retinal abnormalities in humans and implicate lysosomal dysfunction as a central disease process in GRN-associated FTD and GRN-associated NCL.
- Subjects :
- Heterozygote
Aging
Cells
Haploinsufficiency
Neurodegenerative
Electron
Medical and Health Sciences
Retina
Mice
Progranulins
Rare Diseases
Neuronal Ceroid-Lipofuscinoses
mental disorders
Acquired Cognitive Impairment
Animals
Humans
2.1 Biological and endogenous factors
Aetiology
Alzheimer's Disease Related Dementias (ADRD)
Pediatric
Microscopy
Cultured
Neurosciences
Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)
Batten Disease
Biological Sciences
Frontal Lobe
Brain Disorders
Frontotemporal Dementia (FTD)
Orphan Drug
Frontotemporal Dementia
Mutation
Neurological
Intercellular Signaling Peptides and Proteins
Dementia
Lysosomes
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Science translational medicine, vol 9, iss 385
- Accession number :
- edsair.dedup.wf.001..38f9c8b87247446f019bc57204e1f9ff