Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency

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

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish (US)
Article numberddt534
Pages (from-to)1467-1478
Number of pages12
JournalHuman Molecular Genetics
Volume23
Issue number6
DOIs
StatePublished - Mar 2014

Fingerprint

Haploinsufficiency
Frontotemporal Dementia
Endocytosis
Frontotemporal Lobar Degeneration
Neurons
Lymphocytes
Cell Line
Mutation
sortilin
Therapeutics

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency. / Lee, Wing C.; Almeida, Sandra; Prudencio, Mercedes; Caulfield, Thomas; Zhang, Yongjie; Tay, William M.; Bauer, Peter O.; Chew, Jeannie; Sasaguri, Hiroki; Jansen-west, Karen R.; Gendron, Tania D; Stetler, Caroline T.; Finch, NiCole; Mackenzie, Ian R.; Rademakers, Rosa V; Gao, Fen Biao; Petrucelli, Leonard.

In: Human Molecular Genetics, Vol. 23, No. 6, ddt534, 03.2014, p. 1467-1478.

Research output: Contribution to journalArticle

Lee, WC, Almeida, S, Prudencio, M, Caulfield, T, Zhang, Y, Tay, WM, Bauer, PO, Chew, J, Sasaguri, H, Jansen-west, KR, Gendron, TD, Stetler, CT, Finch, N, Mackenzie, IR, Rademakers, RV, 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
Lee, Wing C. ; Almeida, Sandra ; Prudencio, Mercedes ; Caulfield, Thomas ; Zhang, Yongjie ; Tay, William M. ; Bauer, Peter O. ; Chew, Jeannie ; Sasaguri, Hiroki ; Jansen-west, Karen R. ; Gendron, Tania D ; Stetler, Caroline T. ; Finch, NiCole ; Mackenzie, Ian R. ; Rademakers, Rosa V ; Gao, Fen Biao ; Petrucelli, Leonard. / Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 6. pp. 1467-1478.
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