Retrograde transport of neurotrophin receptor TrkB-FL induced by excitotoxicity regulates Golgi stability and is a target for stroke neuroprotection

AbstractExcitotoxicity, aberrant function of survival pathways dependent on brain-derived neurotrophic factor (BDNF) and disruption of the Golgi complex are shared pathological hallmarks of relevant chronic and acute neurological diseases, including stroke. However, precise interdependence among these mechanisms is not completely defined, a knowledge essential to develop neuroprotective strategies. For ischemic stroke, a leading cause of death, disability and dementia, promising results have been obtained by interfering excitotoxicity, major mechanism of neuronal death in the penumbra area surrounding the infarct. We are exploring neuroprotection by promotion of survival cascades dependent on BDNF binding to full-length tropomyosin-related kinase B (TrkB-FL) receptor, which become aberrant after excitotoxicity induction. We have previously developed a blood-brain barrier (BBB) permeable neuroprotective peptide (MTFL457) containing a TrkB-FL sequence which efficiently prevents receptor processing induced by excitotoxicity and preserves BDNF-dependent pathways in a model of ischemia, where it efficiently decreases infarct size and improves neurological outcome after stroke. In this work, using cellular and animal models, we demonstrate that excitotoxicity-induced TrkB-FL downregulation is secondary to receptor endocytosis, receptor interaction with endosomal protein hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), retrograde transport to the Golgi and disruption of this organelle. Interestingly, peptide MTFL457 efficiently interferes TrkB-FL/Hrs interaction and receptor trafficking, processes required for excitotoxic Golgi fragmentation and TrkB-FL cleavage, demonstrating a central role for TrkB-FL in the control of Golgi stability. These results also suggest the potential of peptide MTFL457 to preserve function of this organelle and of critical neuronal survival pathways in stroke and, probably, other neurodegenerative diseases associated to excitotoxicity.