Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency

Wing C. Lee; Sandra Almeida; Mercedes Prudencio; Thomas R. Caulfield; Yong Jie Zhang; William M. Tay; Peter O. Bauer; Jeannie Chew; Hiroki Sasaguri; Karen R. Jansen-west; Tania F. Gendron; Caroline T. Stetler; Ni Cole Finch; Ian R. Mackenzie; Rosa Rademakers; Fen Biao Gao; Leonard Petrucelli

doi:10.1093/hmg/ddt534

Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency

Wing C. Lee, Sandra Almeida, Mercedes Prudencio, Thomas R. Caulfield, Yong Jie Zhang, William M. Tay, Peter O. Bauer, Jeannie Chew, Hiroki Sasaguri, Karen R. Jansen-west, Tania F. Gendron, Caroline T. Stetler, Ni Cole Finch, Ian R. Mackenzie, Rosa Rademakers, Fen Biao Gao, Leonard Petrucelli

Neuroscience

Research output: Contribution to journal › Article › peer-review

58 Scopus citations

Abstract

Progranulin (GRN) mutations causing haploinsufficiency are a major cause of frontotemporal lobar degeneration (FTLD-TDP). Recent discoveries demonstrating sortilin (SORT1) is a neuronal receptor for PGRN endocytosis and a determinant of plasma PGRN levels portend the development of enhancers targeting the SORT1-PGRN axis. We demonstrate the preclinical efficacy of several approaches through which impairing PGRN's interaction with SORT1 restores extracellular PGRN levels. Our report is the first to demonstrate the efficacy of enhancing PGRN levels in iPSC neurons derived from frontotemporal dementia (FTD) patients with PGRN deficiency. We validate a small molecule preferentially increases extracellular PGRN by reducing SORT1 levels in various mammalian cell lines and patient-derived iPSC neurons and lymphocytes. We further demonstrate that SORT1 antagonists and a small-molecule binder of PGRN_588-593, residues critical for PGRN-SORT1 binding, inhibit SORT1-mediated PGRN endocytosis. Collectively, our data demonstrate that the SORT1-PGRN axis is a viable target for PGRN-based therapy, particularly in FTD-GRN patients.

Original language	English (US)
Article number	ddt534
Pages (from-to)	1467-1478
Number of pages	12
Journal	Human molecular genetics
Volume	23
Issue number	6
DOIs	https://doi.org/10.1093/hmg/ddt534
State	Published - Mar 2014

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

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Lee, W. C., Almeida, S., Prudencio, M., Caulfield, T. R., Zhang, Y. J., Tay, W. M., Bauer, P. O., Chew, J., Sasaguri, H., Jansen-west, K. R., Gendron, T. F., Stetler, C. T., Finch, N. C., Mackenzie, I. R., Rademakers, R., Gao, F. B., & Petrucelli, L. (2014). Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency. Human molecular genetics, 23(6), 1467-1478. Article ddt534. https://doi.org/10.1093/hmg/ddt534

Lee, WC, Almeida, S, Prudencio, M , Caulfield, TR , Zhang, YJ, Tay, WM, Bauer, PO, Chew, J, Sasaguri, H, Jansen-west, KR, Gendron, TF, Stetler, CT, Finch, NC, Mackenzie, IR, Rademakers, R, Gao, FB & Petrucelli, L 2014, 'Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency', Human molecular genetics, vol. 23, no. 6, ddt534, pp. 1467-1478. https://doi.org/10.1093/hmg/ddt534

@article{bef0b3061d9d43dca35c6802e1d1611d,

title = "Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency",

abstract = "Progranulin (GRN) mutations causing haploinsufficiency are a major cause of frontotemporal lobar degeneration (FTLD-TDP). Recent discoveries demonstrating sortilin (SORT1) is a neuronal receptor for PGRN endocytosis and a determinant of plasma PGRN levels portend the development of enhancers targeting the SORT1-PGRN axis. We demonstrate the preclinical efficacy of several approaches through which impairing PGRN's interaction with SORT1 restores extracellular PGRN levels. Our report is the first to demonstrate the efficacy of enhancing PGRN levels in iPSC neurons derived from frontotemporal dementia (FTD) patients with PGRN deficiency. We validate a small molecule preferentially increases extracellular PGRN by reducing SORT1 levels in various mammalian cell lines and patient-derived iPSC neurons and lymphocytes. We further demonstrate that SORT1 antagonists and a small-molecule binder of PGRN588-593, residues critical for PGRN-SORT1 binding, inhibit SORT1-mediated PGRN endocytosis. Collectively, our data demonstrate that the SORT1-PGRN axis is a viable target for PGRN-based therapy, particularly in FTD-GRN patients.",

author = "Lee, {Wing C.} and Sandra Almeida and Mercedes Prudencio and Caulfield, {Thomas R.} and Zhang, {Yong Jie} and Tay, {William M.} and Bauer, {Peter O.} and Jeannie Chew and Hiroki Sasaguri and Jansen-west, {Karen R.} and Gendron, {Tania F.} and Stetler, {Caroline T.} and Finch, {Ni Cole} and Mackenzie, {Ian R.} and Rosa Rademakers and Gao, {Fen Biao} and Leonard Petrucelli",

note = "Funding Information: This work was supported by Mayo Clinic Foundation (L.P.), NIH R01 AG026251, R01 NS 063964-01, R01 NS077402, R01 ES20395-01, R21 NS84528-01J (L.P.), NS065782 (R.R.), NIH R01 AG026251, R01 NS057553 (F.B.G.) and the Consortium for Frontotemporal dementia Research (R.R.) (F.B.G.). Funding to pay the Open Access publication charges for this article was provided by the Mayo Clinic.",

year = "2014",

month = mar,

doi = "10.1093/hmg/ddt534",

language = "English (US)",

volume = "23",

pages = "1467--1478",

journal = "Human molecular genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

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T1 - Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency

AU - Lee, Wing C.

AU - Almeida, Sandra

AU - Prudencio, Mercedes

AU - Caulfield, Thomas R.

AU - Zhang, Yong Jie

AU - Tay, William M.

AU - Bauer, Peter O.

AU - Chew, Jeannie

AU - Sasaguri, Hiroki

AU - Jansen-west, Karen R.

AU - Gendron, Tania F.

AU - Stetler, Caroline T.

AU - Finch, Ni Cole

AU - Mackenzie, Ian R.

AU - Rademakers, Rosa

AU - Gao, Fen Biao

AU - Petrucelli, Leonard

N1 - Funding Information: This work was supported by Mayo Clinic Foundation (L.P.), NIH R01 AG026251, R01 NS 063964-01, R01 NS077402, R01 ES20395-01, R21 NS84528-01J (L.P.), NS065782 (R.R.), NIH R01 AG026251, R01 NS057553 (F.B.G.) and the Consortium for Frontotemporal dementia Research (R.R.) (F.B.G.). Funding to pay the Open Access publication charges for this article was provided by the Mayo Clinic.

PY - 2014/3

Y1 - 2014/3

N2 - Progranulin (GRN) mutations causing haploinsufficiency are a major cause of frontotemporal lobar degeneration (FTLD-TDP). Recent discoveries demonstrating sortilin (SORT1) is a neuronal receptor for PGRN endocytosis and a determinant of plasma PGRN levels portend the development of enhancers targeting the SORT1-PGRN axis. We demonstrate the preclinical efficacy of several approaches through which impairing PGRN's interaction with SORT1 restores extracellular PGRN levels. Our report is the first to demonstrate the efficacy of enhancing PGRN levels in iPSC neurons derived from frontotemporal dementia (FTD) patients with PGRN deficiency. We validate a small molecule preferentially increases extracellular PGRN by reducing SORT1 levels in various mammalian cell lines and patient-derived iPSC neurons and lymphocytes. We further demonstrate that SORT1 antagonists and a small-molecule binder of PGRN588-593, residues critical for PGRN-SORT1 binding, inhibit SORT1-mediated PGRN endocytosis. Collectively, our data demonstrate that the SORT1-PGRN axis is a viable target for PGRN-based therapy, particularly in FTD-GRN patients.

AB - Progranulin (GRN) mutations causing haploinsufficiency are a major cause of frontotemporal lobar degeneration (FTLD-TDP). Recent discoveries demonstrating sortilin (SORT1) is a neuronal receptor for PGRN endocytosis and a determinant of plasma PGRN levels portend the development of enhancers targeting the SORT1-PGRN axis. We demonstrate the preclinical efficacy of several approaches through which impairing PGRN's interaction with SORT1 restores extracellular PGRN levels. Our report is the first to demonstrate the efficacy of enhancing PGRN levels in iPSC neurons derived from frontotemporal dementia (FTD) patients with PGRN deficiency. We validate a small molecule preferentially increases extracellular PGRN by reducing SORT1 levels in various mammalian cell lines and patient-derived iPSC neurons and lymphocytes. We further demonstrate that SORT1 antagonists and a small-molecule binder of PGRN588-593, residues critical for PGRN-SORT1 binding, inhibit SORT1-mediated PGRN endocytosis. Collectively, our data demonstrate that the SORT1-PGRN axis is a viable target for PGRN-based therapy, particularly in FTD-GRN patients.

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JF - Human molecular genetics

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ER -

Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency

Abstract

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