Targeted manipulation of the sortilin–progranulin axis rescues progranulin haploinsufficiency
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 targeti...
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| Format: | Online |
| Language: | English |
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Oxford University Press
2014
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929086/ |
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pubmed-3929086 |
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pubmed-39290862014-02-21 Targeted manipulation of the sortilin–progranulin axis rescues progranulin haploinsufficiency Lee, Wing C. Almeida, Sandra Prudencio, Mercedes Caulfield, Thomas R. Zhang, Yong-Jie Tay, William M. Bauer, Peter O. Chew, Jeannie Sasaguri, Hiroki Jansen-West, Karen R. Gendron, Tania F. Stetler, Caroline T. Finch, NiCole Mackenzie, Ian R. Rademakers, Rosa Gao, Fen-Biao Petrucelli, Leonard Articles 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. Oxford University Press 2014-03-15 2013-10-26 /pmc/articles/PMC3929086/ /pubmed/24163244 http://dx.doi.org/10.1093/hmg/ddt534 Text en © The Author 2013. Published by Oxford University Press. http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Lee, Wing C. Almeida, Sandra Prudencio, Mercedes Caulfield, Thomas R. Zhang, Yong-Jie Tay, William M. Bauer, Peter O. Chew, Jeannie Sasaguri, Hiroki Jansen-West, Karen R. Gendron, Tania F. Stetler, Caroline T. Finch, NiCole Mackenzie, Ian R. Rademakers, Rosa Gao, Fen-Biao Petrucelli, Leonard |
| spellingShingle |
Lee, Wing C. Almeida, Sandra Prudencio, Mercedes Caulfield, Thomas R. Zhang, Yong-Jie Tay, William M. Bauer, Peter O. Chew, Jeannie Sasaguri, Hiroki Jansen-West, Karen R. Gendron, Tania F. Stetler, Caroline T. Finch, NiCole Mackenzie, Ian R. Rademakers, Rosa Gao, Fen-Biao Petrucelli, Leonard Targeted manipulation of the sortilin–progranulin axis rescues progranulin haploinsufficiency |
| author_facet |
Lee, Wing C. Almeida, Sandra Prudencio, Mercedes Caulfield, Thomas R. Zhang, Yong-Jie Tay, William M. Bauer, Peter O. Chew, Jeannie Sasaguri, Hiroki Jansen-West, Karen R. Gendron, Tania F. Stetler, Caroline T. Finch, NiCole Mackenzie, Ian R. Rademakers, Rosa Gao, Fen-Biao Petrucelli, Leonard |
| author_sort |
Lee, Wing C. |
| title |
Targeted manipulation of the sortilin–progranulin axis rescues progranulin haploinsufficiency |
| title_short |
Targeted manipulation of the sortilin–progranulin axis rescues progranulin haploinsufficiency |
| title_full |
Targeted manipulation of the sortilin–progranulin axis rescues progranulin haploinsufficiency |
| title_fullStr |
Targeted manipulation of the sortilin–progranulin axis rescues progranulin haploinsufficiency |
| title_full_unstemmed |
Targeted manipulation of the sortilin–progranulin axis rescues progranulin haploinsufficiency |
| title_sort |
targeted manipulation of the sortilin–progranulin axis rescues progranulin haploinsufficiency |
| description |
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. |
| publisher |
Oxford University Press |
| publishDate |
2014 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929086/ |
| _version_ |
1612059992920162304 |