Progranulin deficiency leads to reduced glucocerebrosidase activity

• DOI: 10.1371/journal.pone.0212382
• Publication Date: 2019-07-10T17:28:41Z
• Authors: Xiaolai Zhou; Daniel H. Paushter; Mitchell D. Pagan; Dongsung Kim; Mariela Nunez Santos; Raquel L. Lieberman; Herman S. Overkleeft; Ying Sun; Marcus B. Smolka; Fenghua Hu
• Keywords: Male; Science; Haploinsufficiency; Cell Line; Mice; 03 medical and health sciences; Progranulins; Neuronal Ceroid-Lipofuscinoses; Animals; Humans; Mice, Knockout; 0303 health sciences; Q; R; Recombinant Proteins; Mice, Inbred C57BL; Disease Models, Animal; HEK293 Cells; Mutation; Medicine; Glucosylceramidase; Female; Frontotemporal Lobar Degeneration; Lysosomes; Research Article

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.