Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

104 Scopus citations


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 diseasemechanisms 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 storagematerial, 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 storagematerial and early retinal abnormalities in humans and implicate lysosomal dysfunction as a central disease process in GRN-Associated FTD and GRN-Associated NCL.

Original languageEnglish (US)
Article numbereaah5642
JournalScience translational medicine
Issue number385
StatePublished - Apr 12 2017

ASJC Scopus subject areas

  • Medicine(all)


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