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Synaptic vesicles dynamics in σ1B adaptin -/- mouse model

dc.contributor.advisorSchu, Peter Prof. Dr.
dc.contributor.authorCandiello, Ermes
dc.titleSynaptic vesicles dynamics in σ1B adaptin -/- mouse modelde
dc.contributor.refereeSchu, Peter Prof. Dr.
dc.description.abstractengThe adaptor protein 1 (AP-1) complex of clathrin-coated vesicles (CCVs) mediates protein transport between the trans-Golgi-network and endosomes. It consists of the two large adaptins γ1 and β1, both of which bind clathrin and accessory proteins, and the two smaller adaptins, μ1 and σ1, both of which bind cargo proteins. Three σ1 adaptin isoforms, A, B, and C, are encoded by separate genes. σ1B is the brain specific isoform and σ1A is the ubiquitous isoform, this also explains the viability of the mice. σ1B -/- mice have impaired spatial memory and AP-1/σ1B deficient humans have a severe mental retardation. σ1B -/- mice have fewer synaptic vesicles (SV), reduced SV recycling, but more synaptic CCV and large endosomes. In this study I analyzed the CCV accumulation in ‘ko’ synapse in order to understand how and why they are formed due to the σ1B-adaptin deficiency. First we found out that the accumulating CCV are endocytotic AP-2 CCV, although it was expected that this class of CCV is reduced, due to the reduction of SV recycling. Moreover, the coat composition of these AP-2 CCVs is altered, and thus, they represent a subpopulation of AP-2 CCVs. Based on these data we developed a model where the accumulation of the AP-2 CCVin ‘ko’ is due to an up-regulated CME or a slow uncoating, suggesting that there could be different sub-populations of AP-2 CCV. We were able to isolate a subpopulation, and it turned out to be a ‘stable’ AP-2 CCV pool, with higher coat stability and thus slower or delayed uncoating. Furthermore, we found that the AP-1/σ1B deficiency leads to alterations in the endosomal Rab5 pathway. AP-1 σ1A and σ1B adaptins regulate the Rab5 cycle, by interacting with several Rab5 effector proteins. This interaction is altered in “ko” synapse, leading to enhanced Rab5 activation and thus enhanced early endosome to endolysosome protein transport and SV protein degradation. These findings demonstrate that AP-1/σ1B deficiency strongly effects the AP-2 CCV endocytotic pathway and its functions indicating an interdependent regulation of AP-1 and AP-2 mediated synaptic vesicle recycling and that AP-1 complexes also regulate the endosomal sorting of SV
dc.contributor.coRefereeSimons, Mikael Prof. Dr.
dc.subject.gerAP-1 adaptin; Clathrin-vesicles; synaptic vesicle reformationde
dc.subject.engAP-1 adaptin; Clathrin-vesicles; synaptic vesicle reformationde
dc.affiliation.instituteGöttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)de
dc.subject.gokfullBiologie (PPN619462639)de

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