| dc.contributor.advisor | Schu, Peter Prof. Dr. | |
| dc.contributor.author | Mishra, Ratnakar | |
| dc.date.accessioned | 2019-06-13T08:32:31Z | |
| dc.date.available | 2019-06-13T08:32:31Z | |
| dc.date.issued | 2019-06-13 | |
| dc.identifier.uri | http://hdl.handle.net/21.11130/00-1735-0000-0003-C12E-0 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7514 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 572 | de |
| dc.title | Mechanisms of synaptic plasticity mediated by Clathrin Adaptor-protein complexes 1 and 2 in mice | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Schu, Peter Prof. Dr. | |
| dc.date.examination | 2019-05-14 | |
| dc.description.abstracteng | Clathrin adaptor protein complexes 1 and 2 (AP1 and AP2) have essential functions in synaptic vesicle (SV) recycling. In all cell types and tissues, AP1 mediates TGN/endosome protein sorting via clathrin-coated-vesicles (CCV), whereas AP2 transports proteins by clathrin-mediated endocytosis (CME). Both AP complexes are heterotetrameric, made of four adaptins. Neurons express the ubiquitous AP1/σ1A complex and in addition, the tissue-specific AP1/σ1B complex. In our lab, we have generated σ1B-/- mice. The deficiency of σ1B adaptin leads to severe learning, memory and motor coordination deficits in the knockout mice. σ1B knockout mice are also a model for a severe X-linked mental retardation disease in humans, where the σ1B gene has a premature STOP codon. Synapses lacking the AP1/σ1B complex, display two major phenotypes. Firstly, synaptic vesicle (SV) recycling is impaired, and early endosomes accumulate. The ubiquitous AP1/σ1A complex binds to these endosomes and stimulates their maturation into late, multi-vesicular-body endosomes, up regulating endolysosomal protein transport. Secondly, the endocytic AP2 CCV accumulate, a surprise given the reduction in the major vesicular transport route, SV recycling. This indicated that CME is a major mechanism of synaptic plasticity. AP2 CCV accumulation could be caused by up-regulation of CME or by the stabilization of AP2 CCV extending their half-life.
In this project, I have biochemically characterized these AP2 CCV and demonstrated that two populations of AP2 CCV exist in synapses. One formed by canonical clathrin-mediated-endocytosis (CME) and the other one formed by a specialized pathway, which is characterized by a stabilized CCV coat. Both CME routes are upregulated two-fold in AP1/σ1B deficient synapses. In addition, the longer-lived AP2 CCV of the AP1/σ1B-/- synapses are stabilized by three distinct molecular mechanisms compared to the respective AP2 CCV from wt synapses. The stabilized AP2 CCV of AP1/σ1B-/- synapses are enriched in the active zone proteins, Stonin2 and Git1. The AP1/σ1B deficient synapses contain more Git1 than wild-type synapses, indicating alterations in the dynamics of the active zone in these synapses. Thus, two CME routes characterized by specific lifetimes and specific cargo proteins contribute to synaptic plasticity. | de |
| dc.contributor.coReferee | Schmitt, Hans Dieter Dr. | |
| dc.contributor.thirdReferee | Bayer, Thomas A. Prof. Dr. | |
| dc.contributor.thirdReferee | Rizzoli, Silvio O. Prof. Dr. | |
| dc.contributor.thirdReferee | Oppermann, Martin Prof. Dr. | |
| dc.contributor.thirdReferee | Dosch, Roland Dr. | |
| dc.subject.eng | AP1S2,AP-1,AP-2, Clathrin-coated vesicles (CCV), Synaptic plasticity, Mice, Stabilized AP-2 CCV, Clathrin mediated endocytosis | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-21.11130/00-1735-0000-0003-C12E-0-8 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 1667430637 | |