Back to Search Start Over

Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis

Authors :
Ward, Michael E
Chen, Robert
Huang, Hsin-Yi
Ludwig, Connor
Telpoukhovskaia, Maria
Taubes, Ali
Boudin, Helene
Minami, Sakura S
Reichert, Meredith
Albrecht, Philipp
Gelfand, Jeffrey M
Cruz-Herranz, Andres
Cordano, Christian
Alavi, Marcel V
Leslie, Shannon
Seeley, William W
Miller, Bruce L
Bigio, Eileen
Mesulam, Marek-Marsel
Bogyo, Matthew S
Mackenzie, Ian R
Staropoli, John F
Cotman, Susan L
Huang, Eric J
Gan, Li
Green, Ari J
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.

Details

Database :
OpenAIRE
Journal :
Science translational medicine, vol 9, iss 385
Accession number :
edsair.dedup.wf.001..38f9c8b87247446f019bc57204e1f9ff