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Prosaposin is a regulator of progranulin levels and oligomerization

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 Dye, 2016. "Prosaposin is a regulator of progranulin levels and oligomerization," Nature Communications, Nature, vol. 7(1), pages 1-14, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11992
    DOI: 10.1038/ncomms11992
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    Cited by:

    1. Sebastian Boland & Sharan Swarup & Yohannes A. Ambaw & Pedro C. Malia & Ruth C. Richards & Alexander W. Fischer & Shubham Singh & Geetika Aggarwal & Salvatore Spina & Alissa L. Nana & Lea T. Grinberg , 2022. "Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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