Progranulin deficiency leads to reduced glucocerebrosidase activity.

TitleProgranulin deficiency leads to reduced glucocerebrosidase activity.
Publication TypeJournal Article
Year of Publication2019
AuthorsZhou, X, Paushter, DH, Pagan, MD, Kim, D, Santos, MNunez, Lieberman, RL, Overkleeft, HS, Sun, Y, Smolka, MB, Hu, F
JournalPLoS One
Volume14
Issue7
Paginatione0212382
Date Published2019
ISSN1932-6203
KeywordsAnimals, Cell Line, Disease Models, Animal, Female, Frontotemporal Lobar Degeneration, Glucosylceramidase, Haploinsufficiency, HEK293 Cells, Humans, Lysosomes, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Neuronal Ceroid-Lipofuscinoses, Progranulins, Recombinant Proteins
Abstract

Mutation in the GRN gene, encoding the progranulin (PGRN) protein, shows a dose-dependent disease correlation, wherein haploinsufficiency results in frontotemporal lobar degeneration (FTLD) and complete loss results in neuronal ceroid lipofuscinosis (NCL). Although the exact function of PGRN is unknown, it has been increasingly implicated in lysosomal physiology. Here we report that PGRN interacts with the lysosomal enzyme, glucocerebrosidase (GCase), and is essential for proper GCase activity. GCase activity is significantly reduced in tissue lysates from PGRN-deficient mice. This is further evidence that reduced lysosomal hydrolase activity may be a pathological mechanism in cases of GRN-related FTLD and NCL.

DOI10.1371/journal.pone.0212382
Alternate JournalPLoS ONE
PubMed ID31291241
PubMed Central IDPMC6619604
Grant ListF32 AG027647 / AG / NIA NIH HHS / United States
R01 NS088448 / NS / NINDS NIH HHS / United States
R01 NS095954 / NS / NINDS NIH HHS / United States