TitleIndividuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis.
Publication TypeJournal Article
Year of Publication2017
AuthorsWard ME, Chen R, Huang H-Y, Ludwig C, Telpoukhovskaia M, Taubes A, Boudin H, Minami SS, Reichert M, Albrecht P, Gelfand JM, Cruz-Herranz A, Cordano C, Alavi MV, Leslie S, Seeley WW, Miller BL, Bigio E, Mesulam M-M, Bogyo MS, Mackenzie IR, Staropoli JF, Cotman SL, Huang EJ, Gan L, Green AJ
JournalSci Transl Med
Date Published2017 04 12
KeywordsAnimals, Cells, Cultured, Frontal Lobe, Frontotemporal Dementia, Haploinsufficiency, Heterozygote, Humans, Intercellular Signaling Peptides and Proteins, Lysosomes, Mice, Microscopy, Electron, Mutation, Neuronal Ceroid-Lipofuscinoses, Retina

Heterozygous mutations in the gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal dementia (FTD), a neurodegenerative syndrome of older adults. Homozygous 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 mutation carriers. Increased lipofuscinosis and intracellular NCL-like storage material also occurred in postmortem cortex of heterozygous mutation carriers. Lymphoblasts from heterozygous mutation carriers accumulated prominent NCL-like storage material, which could be rescued by normalizing PGRN expression. Fibroblasts from heterozygous 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 -associated FTD and -associated NCL.

Alternate JournalSci Transl Med
PubMed ID28404863
PubMed Central IDPMC5526610
Grant ListP30 AG013854 / AG / NIA NIH HHS / United States
P50 AG023501 / AG / NIA NIH HHS / United States
I01 BX001108 / BX / BLRD VA / United States
R01 AG036884 / AG / NIA NIH HHS / United States
I01 BX002978 / BX / BLRD VA / United States
R01 NS073813 / NS / NINDS NIH HHS / United States
UL1 TR001422 / TR / NCATS NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States
R01 AG051390 / AG / NIA NIH HHS / United States
R01 NS098516 / NS / NINDS NIH HHS / United States
I01 RX002133 / RX / RRD VA / United States
ZIA NS003155-01 / / NULL / International
K08 EY023610 / EY / NEI NIH HHS / United States
Z99 NS999999 / / NULL / International