Prosaposin is a regulator of progranulin levels and oligomerization

Alexandra M. Nicholson, Ni Cole 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 & 20 others 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, Rosa Rademakers

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Article number11992
JournalNature Communications
Volume7
DOIs
StatePublished - Jun 30 2016

Fingerprint

Oligomerization
regulators
proteins
Proteins
loci
mutations
Blood Proteins
Haploinsufficiency
Frontotemporal Dementia
Mutation
Parkinson disease
Plasmas
genome
fibroblasts
Fibroblasts
Parkinson Disease
oligomers
Oligomers
Alzheimer Disease

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Nicholson, A. M., Finch, N. C. A., Almeida, M., Perkerson, R. B., Van Blitterswijk, M., Wojtas, A., ... Rademakers, R. (2016). Prosaposin is a regulator of progranulin levels and oligomerization. Nature Communications, 7, [11992]. https://doi.org/10.1038/ncomms11992

Prosaposin is a regulator of progranulin levels and oligomerization. / Nicholson, Alexandra M.; Finch, Ni Cole A; Almeida, Marcio; Perkerson, Ralph B.; Van Blitterswijk, Marka; Wojtas, Aleksandra; Cenik, Basar; Rotondo, Sergio; Inskeep, Venette; Almasy, Laura; Dyer, Thomas; Peralta, Juan; Jun, Goo; Wood, Andrew R.; Frayling, Timothy M.; Fuchsberger, Christian; Fowler, Sharon; Teslovich, Tanya M.; Manning, Alisa K.; Kumar, Satish; Curran, Joanne; Lehman, Donna; Abecasis, Goncalo; Duggirala, Ravindranath; Pottier, Cyril; Zahir, Haaris A.; Crook, Julia E.; Karydas, Anna; Mitic, Laura; Sun, Ying; Dickson, Dennis W.; Bu, Guojun; Herz, Joachim; Yu, Gang; Miller, Bruce L.; Ferguson, Shawn; Petersen, Ronald C.; Graff-Radford, Neill; Blangero, John; Rademakers, Rosa.

In: Nature Communications, Vol. 7, 11992, 30.06.2016.

Research output: Contribution to journalArticle

Nicholson, AM, Finch, NCA, Almeida, M, Perkerson, RB, Van Blitterswijk, M, Wojtas, A, Cenik, B, Rotondo, S, Inskeep, V, Almasy, L, Dyer, T, Peralta, J, Jun, G, Wood, AR, Frayling, TM, Fuchsberger, C, Fowler, S, Teslovich, TM, Manning, AK, Kumar, S, Curran, J, Lehman, D, Abecasis, G, Duggirala, R, Pottier, C, Zahir, HA, Crook, JE, Karydas, A, Mitic, L, Sun, Y, Dickson, DW, Bu, G, Herz, J, Yu, G, Miller, BL, Ferguson, S, Petersen, RC, Graff-Radford, N, Blangero, J & Rademakers, R 2016, 'Prosaposin is a regulator of progranulin levels and oligomerization', Nature Communications, vol. 7, 11992. https://doi.org/10.1038/ncomms11992
Nicholson AM, Finch NCA, Almeida M, Perkerson RB, Van Blitterswijk M, Wojtas A et al. Prosaposin is a regulator of progranulin levels and oligomerization. Nature Communications. 2016 Jun 30;7. 11992. https://doi.org/10.1038/ncomms11992
Nicholson, Alexandra M. ; Finch, Ni Cole A ; Almeida, Marcio ; Perkerson, Ralph B. ; Van Blitterswijk, Marka ; Wojtas, Aleksandra ; Cenik, Basar ; Rotondo, Sergio ; Inskeep, Venette ; Almasy, Laura ; Dyer, Thomas ; Peralta, Juan ; Jun, Goo ; Wood, Andrew R. ; Frayling, Timothy M. ; Fuchsberger, Christian ; Fowler, Sharon ; Teslovich, Tanya M. ; Manning, Alisa K. ; Kumar, Satish ; Curran, Joanne ; Lehman, Donna ; Abecasis, Goncalo ; Duggirala, Ravindranath ; Pottier, Cyril ; Zahir, Haaris A. ; Crook, Julia E. ; Karydas, Anna ; Mitic, Laura ; Sun, Ying ; Dickson, Dennis W. ; Bu, Guojun ; Herz, Joachim ; Yu, Gang ; Miller, Bruce L. ; Ferguson, Shawn ; Petersen, Ronald C. ; Graff-Radford, Neill ; Blangero, John ; Rademakers, Rosa. / Prosaposin is a regulator of progranulin levels and oligomerization. In: Nature Communications. 2016 ; Vol. 7.
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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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AU - Nicholson, Alexandra M.

AU - Finch, Ni Cole A

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AU - Perkerson, Ralph B.

AU - Van Blitterswijk, Marka

AU - Wojtas, Aleksandra

AU - Cenik, Basar

AU - Rotondo, Sergio

AU - Inskeep, Venette

AU - Almasy, Laura

AU - Dyer, Thomas

AU - Peralta, Juan

AU - Jun, Goo

AU - Wood, Andrew R.

AU - Frayling, Timothy M.

AU - Fuchsberger, Christian

AU - Fowler, Sharon

AU - Teslovich, Tanya M.

AU - Manning, Alisa K.

AU - Kumar, Satish

AU - Curran, Joanne

AU - Lehman, Donna

AU - Abecasis, Goncalo

AU - Duggirala, Ravindranath

AU - Pottier, Cyril

AU - Zahir, Haaris A.

AU - Crook, Julia E.

AU - Karydas, Anna

AU - Mitic, Laura

AU - Sun, Ying

AU - Dickson, Dennis W.

AU - Bu, Guojun

AU - Herz, Joachim

AU - Yu, Gang

AU - Miller, Bruce L.

AU - Ferguson, Shawn

AU - Petersen, Ronald C.

AU - Graff-Radford, Neill

AU - Blangero, John

AU - Rademakers, Rosa

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