title: Prosaposin is a regulator of progranulin levels and oligomerization.
abstract: Progranulin (GRN) loss-of-function mutations leading to progranulin protein (PGRN) haploinsufficiency are prevalent genetic causes of frontotemporal dementia. Reports also indicated PGRN-mediated neuroprotection in models of Alzheimer's and Parkinson's disease; thus, increasing PGRN levels is a promising therapeutic for multiple disorders. To uncover novel PGRN regulators, we linked whole-genome sequence data from 920 individuals with plasma PGRN levels and identified the prosaposin (PSAP) locus as a new locus significantly associated with plasma PGRN levels. Here we show that both PSAP reduction and overexpression lead to significantly elevated extracellular PGRN levels. Intriguingly, PSAP knockdown increases PGRN monomers, whereas PSAP overexpression increases PGRN oligomers, partly through a protein-protein interaction. PSAP-induced changes in PGRN levels and oligomerization replicate in human-derived fibroblasts obtained from a GRN mutation carrier, further supporting PSAP as a potential PGRN-related therapeutic target. Future studies should focus on addressing the relevance and cellular mechanism by which PGRN oligomeric species provide neuroprotection.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Nicholson
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: NiCole A
authors.initials: NA
authors.lastname: Finch
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas 78520, USA.
authors.forename: Marcio
authors.initials: M
authors.lastname: Almeida
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Ralph B
authors.initials: RB
authors.lastname: Perkerson
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Marka
authors.initials: M
authors.lastname: van Blitterswijk
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Wojtas
authors.affiliation: Department of Neuroscience, Molecular Genetics, and Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Basar
authors.initials: B
authors.lastname: Cenik
authors.affiliation: Department of Cell Biology and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Rotondo
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio 45229, USA.
authors.forename: Venette
authors.initials: V
authors.lastname: Inskeep
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas 78520, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Almasy
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas 78520, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dyer
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas 78520, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Peralta
authors.affiliation: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: Goo
authors.initials: G
authors.lastname: Jun
authors.affiliation: Genetics of Complex Traits, St Luke's Campus, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Wood
authors.affiliation: Genetics of Complex Traits, St Luke's Campus, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.affiliation: Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Fuchsberger
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Fowler
authors.affiliation: Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Teslovich
authors.affiliation: Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Alisa K
authors.initials: AK
authors.lastname: Manning
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas 78520, USA.
authors.forename: Satish
authors.initials: S
authors.lastname: Kumar
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas 78520, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Curran
authors.affiliation: Department of Medicine/Cardiology and Cellular &Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Lehman
authors.affiliation: Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Goncalo
authors.initials: G
authors.lastname: Abecasis
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas 78520, USA.
authors.forename: Ravindranath
authors.initials: R
authors.lastname: Duggirala
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Cyril
authors.initials: C
authors.lastname: Pottier
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Haaris A
authors.initials: HA
authors.lastname: Zahir
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Crook
authors.affiliation: Memory and Aging Center, Department of Neurology, University of California, San Francisco, California 94143, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Karydas
authors.affiliation: Memory and Aging Center, Department of Neurology, University of California, San Francisco, California 94143, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Mitic
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio 45229, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Dennis W
authors.identifier: 0000-0001-7189-7917
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.affiliation: Department of Molecular Genetics, Neuroscience, Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.affiliation: Department of Molecular Genetics, Neuroscience, Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Yu
authors.affiliation: Memory and Aging Center, Department of Neurology, University of California, San Francisco, California 94143, USA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Department of Cell Biology and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Ferguson
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota 55902, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Neill
authors.initials: N
authors.lastname: Graff-Radford
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas 78520, USA.
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000818:Animals; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057895:Haploinsufficiency; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D000077153:Progranulins; D060066:Protein Interaction Maps; D049231:Saposins / Q000235:genetics*
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; C483345:PSAP protein, human; D000077153:Progranulins; C483344:Psap protein, mouse; D049231:Saposins