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.
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Rd S, Jacksonville, FL 32224, USA.
authors.forename: Wing C
authors.initials: WC
authors.lastname: Lee
authors.forename: Sandra
authors.initials: S
authors.lastname: Almeida
authors.forename: Mercedes
authors.initials: M
authors.lastname: Prudencio
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Caulfield
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Zhang
authors.forename: William M
authors.initials: WM
authors.lastname: Tay
authors.forename: Peter O
authors.initials: PO
authors.lastname: Bauer
authors.forename: Jeannie
authors.initials: J
authors.lastname: Chew
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sasaguri
authors.forename: Karen R
authors.initials: KR
authors.lastname: Jansen-West
authors.forename: Tania F
authors.initials: TF
authors.lastname: Gendron
authors.forename: Caroline T
authors.initials: CT
authors.lastname: Stetler
authors.forename: NiCole
authors.initials: N
authors.lastname: Finch
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Fen-Biao
authors.initials: FB
authors.lastname: Gao
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004705:Endocytosis / Q000187:drug effects*; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology; D014644:Genetic Variation; D057809:HEK293 Cells; D057895:Haploinsufficiency; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D000077153:Progranulins; D011725:Pyridines / Q000494:pharmacology*; D015203:Reproducibility of Results; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D011725:Pyridines; D000099183:Sortilin; C492314:GRN protein, human; C121465:6-methyl-2-(phenylethynyl)pyridine