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Sortilin-Mediated Endocytosis Determines Levels of the Fronto-Temporal Dementia Protein, Progranulin

The most common inherited form of Fronto-Temporal Lobar Degeneration (FTLD) known stems from Progranulin (GRN) mutation, and exhibits TDP-43 plus ubiquitin protein aggregates in brain. Despite the causative role of GRN haploinsufficiency in FTLD-TDP, the neurobiology of this secreted glycoprotein is... Full description

Journal Title: Neuron (Cambridge Mass.), 2010-11-18, Vol.68 (4), p.654-667
Main Author: Hu, Fenghua
Other Authors: Padukkavidana, Thihan , Vægter, Christian B. , Brady, Owen A. , Zheng, Yanqiu , Mackenzie, Ian R. , Feldman, Howard H. , Nykjaer, Anders , Strittmatter, Stephen M.
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
ID: ISSN: 0896-6273
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2990962
title: Sortilin-Mediated Endocytosis Determines Levels of the Fronto-Temporal Dementia Protein, Progranulin
format: Article
creator:
  • Hu, Fenghua
  • Padukkavidana, Thihan
  • Vægter, Christian B.
  • Brady, Owen A.
  • Zheng, Yanqiu
  • Mackenzie, Ian R.
  • Feldman, Howard H.
  • Nykjaer, Anders
  • Strittmatter, Stephen M.
subjects:
  • Article
  • mental disorders
ispartof: Neuron (Cambridge, Mass.), 2010-11-18, Vol.68 (4), p.654-667
description: The most common inherited form of Fronto-Temporal Lobar Degeneration (FTLD) known stems from Progranulin (GRN) mutation, and exhibits TDP-43 plus ubiquitin protein aggregates in brain. Despite the causative role of GRN haploinsufficiency in FTLD-TDP, the neurobiology of this secreted glycoprotein is unclear. Here, we examined PGRN binding to the cell surface. PGRN binds to cortical neurons with high affinity via its C-terminus, and unbiased expression cloning identifies Sortilin (Sort1) as a binding site. Sort1-/- neurons exhibit reduced PGRN binding. In the CNS, Sortilin is expressed by neurons and PGRN is most strongly expressed by activated microglial cells after injury. Sortilin rapidly endocytoses and delivers PGRN to lysosomes. Mice lacking Sortilin have elevations in brain and serum PGRN levels of 2.5- to 5-fold. The 50% PGRN decrease causative in FTLD-TDP cases is mimicked in GRN+/- mice, and is fully normalized by Sort1 ablation. Sortilin-mediated PGRN endocytosis is likely to play a central role in FTLD-TDP pathophysiology
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0896-6273
fulltext: fulltext
issn:
  • 0896-6273
  • 1097-4199
url: Link


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creatorHu, Fenghua ; Padukkavidana, Thihan ; Vægter, Christian B. ; Brady, Owen A. ; Zheng, Yanqiu ; Mackenzie, Ian R. ; Feldman, Howard H. ; Nykjaer, Anders ; Strittmatter, Stephen M.
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descriptionThe most common inherited form of Fronto-Temporal Lobar Degeneration (FTLD) known stems from Progranulin (GRN) mutation, and exhibits TDP-43 plus ubiquitin protein aggregates in brain. Despite the causative role of GRN haploinsufficiency in FTLD-TDP, the neurobiology of this secreted glycoprotein is unclear. Here, we examined PGRN binding to the cell surface. PGRN binds to cortical neurons with high affinity via its C-terminus, and unbiased expression cloning identifies Sortilin (Sort1) as a binding site. Sort1-/- neurons exhibit reduced PGRN binding. In the CNS, Sortilin is expressed by neurons and PGRN is most strongly expressed by activated microglial cells after injury. Sortilin rapidly endocytoses and delivers PGRN to lysosomes. Mice lacking Sortilin have elevations in brain and serum PGRN levels of 2.5- to 5-fold. The 50% PGRN decrease causative in FTLD-TDP cases is mimicked in GRN+/- mice, and is fully normalized by Sort1 ablation. Sortilin-mediated PGRN endocytosis is likely to play a central role in FTLD-TDP pathophysiology
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abstractThe most common inherited form of Fronto-Temporal Lobar Degeneration (FTLD) known stems from Progranulin (GRN) mutation, and exhibits TDP-43 plus ubiquitin protein aggregates in brain. Despite the causative role of GRN haploinsufficiency in FTLD-TDP, the neurobiology of this secreted glycoprotein is unclear. Here, we examined PGRN binding to the cell surface. PGRN binds to cortical neurons with high affinity via its C-terminus, and unbiased expression cloning identifies Sortilin (Sort1) as a binding site. Sort1-/- neurons exhibit reduced PGRN binding. In the CNS, Sortilin is expressed by neurons and PGRN is most strongly expressed by activated microglial cells after injury. Sortilin rapidly endocytoses and delivers PGRN to lysosomes. Mice lacking Sortilin have elevations in brain and serum PGRN levels of 2.5- to 5-fold. The 50% PGRN decrease causative in FTLD-TDP cases is mimicked in GRN+/- mice, and is fully normalized by Sort1 ablation. Sortilin-mediated PGRN endocytosis is likely to play a central role in FTLD-TDP pathophysiology
pmid21092856
doi10.1016/j.neuron.2010.09.034
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