SORLA-mediated trafficking of TrkB enhances the response of neurons to BDNF

PLoS One. 2013 Aug 19;8(8):e72164. doi: 10.1371/journal.pone.0072164. eCollection 2013.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Brain-Derived Neurotrophic Factor / pharmacology
  • Cell Line
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation
  • Humans
  • Huntington Disease / genetics*
  • Huntington Disease / metabolism
  • Huntington Disease / physiopathology
  • LDL-Receptor Related Proteins / genetics
  • LDL-Receptor Related Proteins / metabolism*
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Mice
  • Mice, Transgenic
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Primary Cell Culture
  • Protein Transport
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Receptor, trkB
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Signal Transduction
  • Synapses / drug effects
  • Synapses / genetics

Substances

  • Brain-Derived Neurotrophic Factor
  • LDL-Receptor Related Proteins
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Receptors, LDL
  • SORL1 protein, human
  • Sorl1 protein, mouse
  • BDNF protein, human
  • Protein-Tyrosine Kinases
  • Receptor, trkB
  • tropomyosin-related kinase-B, human

Grants and funding

Funding was provided by: http://www.brightfocus.org/; http://www.fritz-thyssen-stiftung.de/; http://www.carlsberggroup.com/Company/Foundations/Pages/default.aspx; and http://www.dfg.de/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.