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dc.contributor.authorMartynyuk, Nataly
dc.date.accessioned2019-01-14T10:03:31Z
dc.date.available2019-01-14T10:03:31Z
dc.date.issued2019-01-26
dc.date.submitted2018-06-26
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/287938
dc.description.abstractRho GTPases and their regulators such as guanosine exchange factors (GEFs) and GTPase activating proteins (GAPs) represent an important class of molecules controlling dendritic spine plasticity. Although they are typically described as cytoskeletal modulators, roles for the GTPases in endocytosis and cell polarity establishment have also been defined. The neuronal proteins a1- and a2-chimaerins belong to a group of Rac and Cdc42 GAPs that inactivate these GTPases; in addition to a GAP domain, the a-chimaerins share a phosphokinase C (PKC)-like C1 domain but have distinct N-terminal domains (NTDs). My project has explored the importance of specific domains of a1-chimaerin both in induction of a morphological cellular protrusion collapse phenotype (‘circularisation’) and in interactions with partner proteins that may help to explain the phenotype. The results described in my thesis show that a1-chimaerin possesses a previously undescribed C-terminal domain (CTD) that is indispensable for the ability of the protein to induce collapse of protrusions, and consequent circularisation, in various cell types; moreover, an intact CTD is also important for association of a1-chimaerin with its known effector EphA4, and potentially with other undefined membrane proteins, in a C1-domain- dependent manner. In addition, my results show that a1-chimaerin associates via its NTD with the Src kinase Fyn, and via its C1 domain with the NR2A subunit of the NMDA receptor. Further experiments explored a1-chimaerin effects on EphA4 and NMDA receptor cell surface expression, as well as binding to other putative partners – including the adaptor protein p35 and the polarity protein PAR6. Finally, I have shown that inhibition of a pathway involving the Rho-associated coiled-coil containing protein kinase (ROCK) reverts circularisation induced by a1- chimaerin, and that a blocking peptide based on the CTD may be employed to partially counteract the phenotype. These results uncover a novel domain in a1-chimaerin that may have a crucial importance for the induction of cellular process collapse by a1-chimaerin with a potential relevance to the EphA4-induced dendritic spine retraction, EphA4 receptor endocytosis, and cell surface expression of NR2A-containing NMDA receptors. This suggests a model of a multi-protein signalling complex involving a1-chimaerin that coordinates cellular process remodelling, and that is likely to be important both for adult neuronal circuit plasticity and for neurodegenerative diseases.
dc.description.sponsorshipCambridge Trust; Selwyn college
dc.language.isoen
dc.rightsAll rights reserved
dc.rightsAll Rights Reserveden
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved/en
dc.subjectChimaerin
dc.subjectAlpha-chimaerin
dc.subjectDendritic spines
dc.subjectNeurodegeneration
dc.subjectNeuroplasticity
dc.subjectRhoGTPases
dc.subjectRac
dc.subjectRho
dc.subjectGTPase activating proteins
dc.subjectGAP
dc.subjectRacGAP
dc.subjectCdc42
dc.subjectCytoskeleton
dc.subjectEndocytosis
dc.subjectHEK293
dc.subjectHeLa
dc.subjectChimerin
dc.subjectCHIN
dc.subjectROCK
dc.subjectEphA4
dc.subjectC1 domain
dc.titleActions of alpha-chimaerins in mechanisms relevant to dendritic spine formation and neurodegeneration
dc.typeThesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.publisher.institutionUniversity of Cambridge
dc.publisher.departmentClinical Neurosciences
dc.date.updated2019-01-09T15:36:45Z
dc.identifier.doi10.17863/CAM.35253
dc.publisher.collegeSelwyn
dc.type.qualificationtitlePhD in Clinical Neurosciences
cam.supervisorButtery, Philip
cam.thesis.fundingfalse


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