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; 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

doi:10.1038/ncomms11992

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 KumarJoanne 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

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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.

Original language	English (US)
Article number	11992
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11992
State	Published - Jun 30 2016

ASJC Scopus subject areas

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

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

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

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title = "Prosaposin is a regulator of progranulin levels and oligomerization",

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.",

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

note = "Funding Information: We are deeply indebted to Richard Gibson (deceased) for his many years of commitment to science, the Department of Molecular Genetics at UT Southwestern and for his help with producing anti-progranulin antibodies. We thank the T2D-GENES consortium for sequencing data sharing. This work was funded by NIH grants R01 NS076471, P50 AG016574 and UO1 AG006786 awarded to Rosa Rademakers, the Younkin Scholarship awarded to Alexandra Nicholson, and the Consortium for Frontotemporal Degeneration Research. T2D-GENES Consortium is supported by NIH grants U01 DK085524, U01 DK085584, U01 DK085501, U01 DK085526 and U01 DK085545. The San Antonio Family Studies is supported by NIH grants P01 HL045222, R01 DK047482 and R01 DK053889.",

year = "2016",

month = jun,

day = "30",

doi = "10.1038/ncomms11992",

language = "English (US)",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - Prosaposin is a regulator of progranulin levels and oligomerization

AU - Nicholson, Alexandra M.

AU - Finch, Ni Cole A

AU - Almeida, Marcio

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

N1 - Funding Information: We are deeply indebted to Richard Gibson (deceased) for his many years of commitment to science, the Department of Molecular Genetics at UT Southwestern and for his help with producing anti-progranulin antibodies. We thank the T2D-GENES consortium for sequencing data sharing. This work was funded by NIH grants R01 NS076471, P50 AG016574 and UO1 AG006786 awarded to Rosa Rademakers, the Younkin Scholarship awarded to Alexandra Nicholson, and the Consortium for Frontotemporal Degeneration Research. T2D-GENES Consortium is supported by NIH grants U01 DK085524, U01 DK085584, U01 DK085501, U01 DK085526 and U01 DK085545. The San Antonio Family Studies is supported by NIH grants P01 HL045222, R01 DK047482 and R01 DK053889.

PY - 2016/6/30

Y1 - 2016/6/30

N2 - 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.

AB - 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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U2 - 10.1038/ncomms11992

DO - 10.1038/ncomms11992

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SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 11992

ER -

Prosaposin is a regulator of progranulin levels and oligomerization

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