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A role for the truncated trkB receptor in neurons

Fenner, Barbara Murray (2004) A role for the truncated trkB receptor in neurons. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

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.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Fenner, Barbara Murraybamst18@pitt.eduBAMST18
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBowser, Robertbowserrp@upmc.edu
Committee MemberAchim, Cristian Lcrisachim@earthlink.net
Committee MemberBeer-Stolz, Donnadstolz@pitt.eduDSTOLZ
Committee MemberZarnegar, Rezarezazar@pitt.eduREZAZAR
Committee MemberLiu, Yong-Jianyjliu@pitt.eduYJLIU
Date: 22 December 2004
Date Type: Completion
Defense Date: 16 December 2004
Approval Date: 22 December 2004
Submission Date: 21 December 2004
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: BDNF; endosomes; neuron; neurotrophin; Parkinson's diseease; protien transport
Other ID: http://etd.library.pitt.edu/ETD/available/etd-12212004-110446/, etd-12212004-110446
Date Deposited: 10 Nov 2011 20:11
Last Modified: 15 Nov 2016 13:54
URI: http://d-scholarship.pitt.edu/id/eprint/10443

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