Sortilin controls intracellular sorting of brain-derived neurotrophic factor to the regulated secretory pathway.
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.
Department of Psychiatry, Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
Zhe-Yu
ZY
Chen
Alessandro
A
Ieraci
Henry
H
Teng
Henning
H
Dall
Chui-Xiang
CX
Meng
Daniel G
DG
Herrera
Anders
A
Nykjaer
Barbara L
BL
Hempstead
Francis S
FS
Lee
D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D003001:Cloning, Molecular; D005822:Genetic Vectors; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D008568:Memory / Q000502:physiology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D011110:Polymorphism, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D019208:Brain-Derived Neurotrophic Factor; D005982:Glutathione Transferase; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D000099183:Sortilin