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Nat Commun. 2016 Jun 30;7:11992. doi: 10.1038/ncomms11992.

Prosaposin is a regulator of progranulin levels and oligomerization.

Author information

1
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
2
South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas 78520, USA.
3
Department of Neuroscience, Molecular Genetics, and Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
4
Department of Cell Biology and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
5
Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio 45229, USA.
6
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
7
Genetics of Complex Traits, St Luke's Campus, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK.
8
Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
9
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229, USA.
10
Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
11
Department of Medicine/Cardiology and Cellular &Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
12
Memory and Aging Center, Department of Neurology, University of California, San Francisco, California 94143, USA.
13
Department of Molecular Genetics, Neuroscience, Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
14
Department of Neurology, Mayo Clinic, Rochester, Minnesota 55902, USA.
15
Department of Neurology, Mayo Clinic, Jacksonville, Florida 32224, USA.

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.

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