title: Progranulin regulates lysosomal function and biogenesis through acidification of lysosomes.
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.
authors.affiliation: Department of Dementia and Higher Brain function, Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.|Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Dementia and Higher Brain function, Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Genjiro
authors.initials: G
authors.lastname: Suzuki
authors.affiliation: Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuwaki
authors.affiliation: Department of Dementia and Higher Brain function, Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Hosokawa
authors.affiliation: Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City AZ 85351, USA.
authors.forename: Geidy
authors.initials: G
authors.lastname: Serrano
authors.affiliation: Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City AZ 85351, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Beach
authors.affiliation: Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Yamanouchi
authors.affiliation: Department of Dementia and Higher Brain function, Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Masugi
authors.initials: M
authors.lastname: Nishihara
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002402:Cathepsin D / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D057895:Haploinsufficiency / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D008247:Lysosomes / Q000235:genetics / Q000473:pathology; D051379:Mice; D009154:Mutation; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D061251:Primary Cell Culture; D000077153:Progranulins; D011506:Proteins / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D011506:Proteins; C000598624:TARDBP protein, human; C018589:lysosomal proteins; D002402:Cathepsin D