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PLoS One. 2019 Jul 10;14(7):e0212382. doi: 10.1371/journal.pone.0212382. eCollection 2019.

Progranulin deficiency leads to reduced glucocerebrosidase activity.

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Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, United States of America.
School of Chemistry and Biochemistry, Georgia Institute of Technology, NW, Atlanta, GA, United States of America.
Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, RA Leiden, Netherlands.
Division of Human Genetics; Cincinnati Children's Hospital Medical Center and the Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.


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.

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