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Sci Transl Med. 2017 Apr 12;9(385). pii: eaah5642. doi: 10.1126/scitranslmed.aah5642.

Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis.

Author information

1
Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
2
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
3
Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
4
Department of Pathology, University of California, San Francisco, San Francisco, CA 94158, USA.
5
Department of Pathology, National Taiwan University Hospital, Taipei City, Taiwan.
6
INSERM UMR 913, Université de Nantes, Nantes, France.
7
Department of Neurology, Medical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany.
8
Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94158, USA.
9
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
10
Department of Pathology, Stanford Medical School, Palo Alto, CA 94305, USA.
11
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
12
Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
13
Pathology Service, Veterans Affairs Medical Center, San Francisco, CA 94141, USA.
14
Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA. lgan@gladstone.ucsf.edu agreen@ucsf.edu.
15
Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. lgan@gladstone.ucsf.edu agreen@ucsf.edu.

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.

PMID:
28404863
PMCID:
PMC5526610
DOI:
10.1126/scitranslmed.aah5642
[Indexed for MEDLINE]
Free PMC Article

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