RRC ID 65062
Author Tanaka Y, Suzuki G, Matsuwaki T, Hosokawa M, Serrano G, Beach TG, Yamanouchi K, Hasegawa M, Nishihara M.
Title Progranulin regulates lysosomal function and biogenesis through acidification of lysosomes.
Journal Hum Mol Genet
Abstract Progranulin (PGRN) haploinsufficiency resulting from loss-of-function mutations in the PGRN gene causes frontotemporal lobar degeneration accompanied by TDP-43 accumulation, and patients with homozygous mutations in the PGRN gene present with neuronal ceroid lipofuscinosis. Although it remains unknown why PGRN deficiency causes neurodegenerative diseases, there is increasing evidence that PGRN is implicated in lysosomal functions. Here, we show PGRN is a secretory lysosomal protein that regulates lysosomal function and biogenesis by controlling the acidification of lysosomes. PGRN gene expression and protein levels increased concomitantly with the increase of lysosomal biogenesis induced by lysosome alkalizers or serum starvation. Down-regulation or insufficiency of PGRN led to the increased lysosomal gene expression and protein levels, while PGRN overexpression led to the decreased lysosomal gene expression and protein levels. In particular, the level of mature cathepsin D (CTSDmat) dramatically changed depending upon PGRN levels. The acidification of lysosomes was facilitated in cells transfected with PGRN. Then, this caused degradation of CTSDmat by cathepsin B. Secreted PGRN is incorporated into cells via sortilin or cation-independent mannose 6-phosphate receptor, and facilitated the acidification of lysosomes and degradation of CTSDmat. Moreover, the change of PGRN levels led to a cell-type-specific increase of insoluble TDP-43. In the brain tissue of FTLD-TDP patients with PGRN deficiency, CTSD and phosphorylated TDP-43 accumulated in neurons. Our study provides new insights into the physiological function of PGRN and the role of PGRN insufficiency in the pathogenesis of neurodegenerative diseases.
Volume 26(5)
Pages 969-988
Published 2017-3-1
DOI 10.1093/hmg/ddx011
PII ddx011
PMID 28073925
MeSH Animals Brain / metabolism Brain / pathology Cathepsin D / genetics* Cathepsin D / metabolism DNA-Binding Proteins / genetics* DNA-Binding Proteins / metabolism Frontotemporal Lobar Degeneration / genetics* Frontotemporal Lobar Degeneration / metabolism Frontotemporal Lobar Degeneration / pathology Gene Expression Regulation Haploinsufficiency / genetics Humans Intercellular Signaling Peptides and Proteins / biosynthesis Intercellular Signaling Peptides and Proteins / genetics* Lysosomes / genetics Lysosomes / pathology Mice Mutation Neuroblastoma / metabolism Neurons / metabolism* Neurons / pathology Primary Cell Culture Progranulins Proteins / genetics
IF 5.101
Human and Animal Cells MG6(RCB2403)