Prosaposin is a regulator of progranulin levels and oligomerization

Alexandra M. Nicholson, NiCole A. Finch, Marcio Almeida, Ralph B. Perkerson, Marka van Blitterswijk, Aleksandra Wojtas, Basar Cenik, Sergio Rotondo, Venette Inskeep, Laura Almasy, Thomas Dyer, Juan Peralta, Goo Jun, Andrew R. Wood, Timothy M. Frayling, Christian Fuchsberger, Sharon Fowler, Tanya M. Teslovich, Alisa K. Manning, Satish Kumar, Joanne Curran, Donna Lehman, Goncalo Abecasis, Ravindranath Duggirala, Cyril Pottier, Haaris A. Zahir, Julia E. Crook, Anna Karydas, Laura Mitic, Ying Sun, Dennis W. Dickson, Guojun Bu, Joachim Herz, Gang Yu, Bruce L. Miller, Shawn Ferguson, Ronald C. Petersen, Neill Graff-Radford, John Blangero and Rosa Rademakers ()
Additional contact information
Alexandra M. Nicholson: Mayo Clinic
NiCole A. Finch: Mayo Clinic
Marcio Almeida: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine
Ralph B. Perkerson: Mayo Clinic
Marka van Blitterswijk: Mayo Clinic
Aleksandra Wojtas: Mayo Clinic
Basar Cenik: Molecular Genetics, and Psychiatry, University of Texas Southwestern Medical Center
Sergio Rotondo: Neurodegeneration and Repair, Yale University School of Medicine
Venette Inskeep: Cincinnati Children’s Hospital Research Foundation
Laura Almasy: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine
Thomas Dyer: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine
Juan Peralta: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine
Goo Jun: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston
Andrew R. Wood: Genetics of Complex Traits, St Luke’s Campus, University of Exeter Medical School, University of Exeter
Timothy M. Frayling: Genetics of Complex Traits, St Luke’s Campus, University of Exeter Medical School, University of Exeter
Christian Fuchsberger: Center for Statistical Genetics, University of Michigan
Sharon Fowler: University of Texas Health Science Center
Tanya M. Teslovich: Center for Statistical Genetics, University of Michigan
Alisa K. Manning: Center for Human Genetics Research, Massachusetts General Hospital
Satish Kumar: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine
Joanne Curran: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine
Donna Lehman: University of Texas Health Science Center at San Antonio
Goncalo Abecasis: Center for Statistical Genetics, University of Michigan
Ravindranath Duggirala: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine
Cyril Pottier: Mayo Clinic
Haaris A. Zahir: Mayo Clinic
Julia E. Crook: Mayo Clinic
Anna Karydas: Memory and Aging Center, University of California
Laura Mitic: Memory and Aging Center, University of California
Ying Sun: Cincinnati Children’s Hospital Research Foundation
Dennis W. Dickson: Mayo Clinic
Guojun Bu: Mayo Clinic
Joachim Herz: Neuroscience, Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center
Gang Yu: Neuroscience, Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center
Bruce L. Miller: Memory and Aging Center, University of California
Shawn Ferguson: Neurodegeneration and Repair, Yale University School of Medicine
Ronald C. Petersen: Mayo Clinic
Neill Graff-Radford: Mayo Clinic
John Blangero: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine
Rosa Rademakers: Mayo Clinic

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11992

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