Excitotoxicity, 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 t... More
Excitotoxicity, 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.
