A role for the truncated trkB receptor in neurons

[摘要] Brain derived neurotrophic factor (BDNF) promotes cell survival, proliferation, differentiation, and enhances neurotransmission. In several neurodegenerative diseases, including Parkinson's disease (PD), BDNF mRNA and protein are altered in regions of pathology. The cellular response to BDNF is mediated by trkB. There are two trkB receptor isoforms abundantly expressed in the brain, full-length (fl) and truncated trkB (tc). TrkB.fl is a tyrosine kinase receptor that activates intracellular signaling cascades. Although the extracellular and transmembrane domains of trkB.tc are 100% homologous to trkB.fl, its intracellular domain is unique and lacks the catalytic amino acids. TrkB.fl functions as a signaling receptor while trkB.tc binds to and internalizes BDNF. The intracellular function of trkB.tc is unclear because it lacks the cytoplasmic signaling domain. The purpose of this dissertation was to identify a novel role for the truncated trkB receptor in mature neurons of the central nervous system. Our study had two goals: 1) to investigate the hypothesis that trkB.tc facilitates the endocytic sorting of BDNF and 2) to investigate the changes in trkB.tc protein distribution in PD. Finally, we correlated the changes in trkB.tc distribution in PD with its potential role in BDNF transport. Our organelle studies revealed co-localization of trkB.tc and internalized BDNF within endosomes, showing that the two proteins were transported as a complex. This protein complex is maintained within recycling endosomes. Although we did see co-localization of trkB.tc and internalized BDNF within lysosomes, it was not as extensive as the sorting of BDNF to recycling vesicles endosomes. Immunofluorescence studies of human autopsy striatum and substantia nigra revealed that trkB.tc and trkB.fl are differentially distributed in the control and PD brains. Furthermore, changes in the distribution of both trkB isoforms are seen in PD and correspond to regions of pathology. We conclude that upregulation of striatal trkB.tc in PD is an early response to neurodegeneration and regulates the effects of BDNF. In summary, trkB.tc facilitates the intracellular sorting of internalized BDNF to recycling endosomes. The altered distribution of trkB.tc in PD suggests enhanced trkB.tc transport, and potentially BDNF transport. This may enhance the neuroprotective effects of BDNF in PD.

[发布机构] the University of Pittsburgh

[效力级别] endosomes