Abstract
Stimulation of neurons with brain-derived neurotrophic factor (BDNF) results in robust induction of SORLA, an intracellular sorting receptor of the VPS10P domain receptor gene family. However, the relevance of SORLA for BDNF-induced neuronal responses has not previously been investigated. We now demonstrate that SORLA is a sorting factor for the tropomyosin-related kinase receptor B (TrkB) that facilitates trafficking of this BDNF receptor between synaptic plasma membranes, post-synaptic densities, and cell soma, a step critical for neuronal signal transduction. Loss of SORLA expression results in impaired neuritic transport of TrkB and in blunted response to BDNF in primary neurons; and it aggravates neuromotoric deficits caused by low BDNF activity in a mouse model of Huntington's disease. Thus, our studies revealed a key role for SORLA in mediating BDNF trophic signaling by regulating the intracellular location of TrkB.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Brain-Derived Neurotrophic Factor / metabolism*
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Brain-Derived Neurotrophic Factor / pharmacology
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Cell Line
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Disease Models, Animal
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Female
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Gene Expression Regulation
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Humans
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Huntington Disease / genetics*
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Huntington Disease / metabolism
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Huntington Disease / physiopathology
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LDL-Receptor Related Proteins / genetics
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LDL-Receptor Related Proteins / metabolism*
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Male
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Membrane Transport Proteins / genetics
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Membrane Transport Proteins / metabolism*
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Mice
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Mice, Transgenic
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism*
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Primary Cell Culture
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Protein Transport
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Receptor, trkB
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Receptors, LDL / genetics
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Receptors, LDL / metabolism*
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Signal Transduction
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Synapses / drug effects
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Synapses / genetics
Substances
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Brain-Derived Neurotrophic Factor
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LDL-Receptor Related Proteins
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Membrane Glycoproteins
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Membrane Transport Proteins
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Receptors, LDL
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SORL1 protein, human
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Sorl1 protein, mouse
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BDNF protein, human
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Protein-Tyrosine Kinases
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Receptor, trkB
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tropomyosin-related kinase-B, human