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PMID: 15987945 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Sortilin controls intracellular sorting of brain-derived neurotrophic factor to the regulated secretory pathway.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 25 ·No. 26 ·2005-06-29 ·Pages 6156-66

Chen ZY, Ieraci A, Teng H, Dall H, Meng CX, Herrera DG, Nykjaer A, Hempstead BL, Lee FS

Abstract

Brain-derived neurotrophic factor (BDNF), after activity-dependent secretion from neurons, modulates critical nervous system functions. Recently, a variant in the human bdnf gene, resulting in a valine to methionine substitution in the prodomain, has been shown to lead to defective regulated secretion from neurons and memory impairment. Here, we report a novel function for a Vps10p domain protein, sortilin, in controlling BDNF sorting to the regulated secretory pathway. Sortilin interacts specifically with BDNF in a region encompassing the methionine substitution and colocalizes with BDNF in secretory granules in neurons. A truncated form of sortilin causes BDNF missorting to the constitutive secretory pathway without affecting neurotrophin-4 (NT-4) secretion. In addition, sortilin small interfering RNA introduced into primary neurons also led to BDNF missorting from the regulated to the constitutive secretory pathway. Together, these data suggest a mechanism to understand the defect associated with variant BDNF and provide a framework, based on divergent presynaptic regulation of sorting to secretory pathways, to explain how two ligands for tropomyosin-related kinase B, BDNF and NT-4, can mediate diverse biological responses.

MeSH Terms
Adaptor Proteins, Vesicular Transport Animals Brain-Derived Neurotrophic Factor/genetics,physiology Cell Line Cloning, Molecular Genetic Vectors Glutathione Transferase/metabolism Humans Immunohistochemistry Membrane Glycoproteins/genetics,physiology Memory/physiology Mice Nerve Tissue Proteins/genetics,physiology Neurons/physiology Polymorphism, Genetic RNA, Small Interfering/genetics Recombinant Proteins/metabolism
Chemicals
Adaptor Proteins, Vesicular Transport Brain-Derived Neurotrophic Factor Membrane Glycoproteins Nerve Tissue Proteins RNA, Small Interfering Recombinant Proteins Glutathione Transferase sortilin
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Chen Zhe-Yu
Department of Psychiatry, Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
Ieraci Alessandro
Teng Henry
Dall Henning
Meng Chui-Xiang
Herrera Daniel G
Nykjaer Anders
Hempstead Barbara L
Lee Francis S
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.1017-05.2005
Published
2005-06-29
Pages
6156-66
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC1201519
Subset
IM
Grants
NINDS NIH HHS · R01 NS030687 · United States
NINDS NIH HHS · R01 NS052819 · United States
NINDS NIH HHS · NS052819 · United States
NINDS NIH HHS · NS30687 · United States
External Links
PubMed source DOI: 10.1523/JNEUROSCI.1017-05.2005 PMC Full Text View journal details
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