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Prosaposin is a regulator of progranulin levels and oligomerization

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Nicholson, Alexandra M., Finch, NiCole A., Almeida, Marcio, Perkerson, Ralph B., van Blitterswijk, Marka, Wojtas, Aleksandra, Cenik, Basar, Rotondo, Sergio +32 more·2016·Nature Communications
DOI 10.1038/ncomms11992PMC PMC4931318
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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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  • Prosaposin heterodimerizes with progranulin, regulating its levels and facilitating its transport to the lysosome.

    “Prosaposin heterodimerizes with progranulin, regulating its levels and facilitating its transport to the lysosome35,36.”

    From Rare variant associations with plasma protein levels in the UK Biobank (2023) · cites this paper as [36]

    The Results (PSAP–PGRN interaction; page unavailable) show that prosaposin binds progranulin, and the paper reports that prosaposin regulates progranulin levels. But the Results describe a prosaposin–progranulin heterodimer as a possibility, not an established fact. The Discussion (page unavailable) says prosaposin itself is transported to lysosomes; it does not establish that prosaposin facilitates progranulin’s transport there. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

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Authors
Nicholson, A. M., Finch, N. A., Almeida, M., Perkerson, R. B., van Blitterswijk, M., Wojtas, A., Cenik, B., Rotondo, S., Inskeep, V., Almasy, L., Dyer, T., Peralta, J., Jun, G., Wood, A. R., Frayling, T. M., Fuchsberger, C., Fowler, S., Teslovich, T. M., Manning, A. K., Kumar, S., Curran, J., Lehman, D., Abecasis, G., Duggirala, R., Pottier, C., Zahir, H. A., Crook, J. E., Karydas, A., Mitic, L., Sun, Y., Dickson, D. W., Bu, G., Herz, J., Yu, G., Miller, B. L., Ferguson, S., Petersen, R. C., Graff-Radford, N., Blangero, J., & Rademakers, R.
Affiliations
  • Mayo Clinic (US)
  • The University of Texas Rio Grande Valley (US)
  • The University of Texas Southwestern Medical Center (US)
  • Yale University (US)
  • Cincinnati Children's Hospital Medical Center (US)
  • The University of Texas Health Science Center at Houston (US)
  • University of Exeter (GB)
  • University of Michigan (US)
  • The University of Texas at San Antonio Health Science Center (US)
  • Massachusetts General Hospital (US)
  • University of California, San Francisco (US)
Corresponding author
Rademakers, Rosa
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2016-06-30
Volume
7
Issue
1
Pages
11992-11992
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms11992
PMC
PMC4931318
OpenAlex
W2463238622
Cited by
91
References
2
Citations by year
2026: 8 · 2025: 6 · 2024: 8 · 2023: 8 · 2022: 11 · 2021: 16 · 2020: 10 · 2019: 9 · 2018: 5 · 2017: 10
FWCI
6.02
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ScholarWorks @ UTRGV (The University of Texas Rio Grande Valley) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
  • University of Texas Southwestern Medical Center
  • National Institutes of Health (P01 HL045222, AG016574, DK047482, DK085501, DK085584, AG006786)
  • National Institute on Aging (U01AG006786, P50AG016574)
  • National Heart, Lung, and Blood Institute (R37HL063762)
  • National Institute of Diabetes and Digestive and Kidney Diseases (U01DK085526, U01DK085584, U01DK085501, U01DK085524, U01DK085545, R01DK047482, R01DK053889)
  • National Institute of Neurological Disorders and Stroke (R01NS076471, R01NS093382)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
prosaposin, progranulin, frontotemporal dementia, GRN mutations, protein-protein interaction, neuroprotection, therapeutic target, fibroblasts
MeSH terms
Progranulins, Alzheimer Disease, Animals, HeLa Cells, Humans, Parkinson Disease, Mice, Knockout, Polymorphism, Single Nucleotide, Intercellular Signaling Peptides and Proteins, Saposins, Mice, Gene Knockdown Techniques, Frontotemporal Dementia, Haploinsufficiency, Protein Interaction Maps

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