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The Journal of Neuroscience, June 29, 2005, 25(26):6156-6166; doi:10.1523/JNEUROSCI.1017-05.2005

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Cellular/Molecular
Sortilin Controls Intracellular Sorting of Brain-Derived Neurotrophic Factor to the Regulated Secretory Pathway

Zhe-Yu Chen,^1,3 Alessandro Ieraci,¹ Henry Teng,² Henning Dall,⁵ Chui-Xiang Meng,⁴ Daniel G. Herrera,¹ Anders Nykjaer,⁵ Barbara L. Hempstead,² and Francis S. Lee¹

¹Department of Psychiatry, and ²Division of Hematology, Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, Departments of ³ Neurobiology and ⁴Basic Medical Sciences, The Second Military Medical University, Shanghai 200433, People's Republic of China, and ⁵Department of Medical Biochemistry, Aarhus University, DK-8000 Aarhus C, Denmark

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.

Key words: brain-derived neurotrophic factor; polymorphism; prodomain; sortilin; intracellular trafficking; regulated secretion

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Received March 15, 2005; revised May 17, 2005; accepted May 18, 2005.

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