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

Abstract

Abstract Excitotoxicity, aberrant function of survival pathways dependent on brain-derived neurotrophic factor (BDNF), and disruption of the Golgi complex are shared pathological hallmarks in relevant neurological diseases, including stroke. However, the precise interdependence among these mechanisms is not completely defined, knowledge essential for developing neuroprotective strategies. For ischemic stroke, a leading cause of death, disability, and dementia, interfering with excitotoxicity—the major mechanism of neuronal death in the penumbra area—has shown promising results. We are exploring neuroprotection by promoting survival cascades dependent on the BDNF receptor, full-length tropomyosin-related kinase B (TrkB-FL), as these pathways become aberrant after excitotoxicity. We previously developed MTFL457, a blood-brain barrier (BBB) permeable neuroprotective peptide containing a TrkB-FL sequence, which efficiently prevents excitotoxicity-induced receptor processing and preserves BDNF-dependent pathways in an ischemia model, where it decreases infarct size and improves neurological outcome. In this work, using cellular and animal models, we demonstrate that excitotoxicity-induced TrkB-FL downregulation is secondary to receptor endocytosis, interaction with the endosomal protein hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), retrograde transport to the Golgi, and subsequent disruption of this organelle. Interestingly, peptide MTFL457 interferes with the 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 controlling Golgi stability. These results suggest the potential for peptide MTFL457 to preserve the function of this organelle and critical neuronal survival pathways in stroke and possibly other neurodegenerative diseases associated with excitotoxicity.