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

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


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
Issue number6
StatePublished - Mar 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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