Role of Alix in endocytosis at presynaptic boutons

Abstract : Neurotransmission involves the fusion of synaptic vesicles (SVs) to the presynaptic membrane to release neurotransmitters that will bind receptors on the postsynaptic neuron. The number of SVs in central nerve terminals is limited, necessitating a set of reliable mechanisms to regenerate SVs. Among such mechanisms are clathrin-mediated endocytosis, ultrafast endocytosis and activity-dependent bulk endocytosis (ADBE), where the latter two are clathrin-independent. The present study reveals that the depletion of Alix (ALG-2 interacting protein-X) leads to morphological and functional changes of synapses that indicate defective SV recycling. Our recent finding that Alix and its major partner, endophilin-A, is crucial for clathrin-independent endocytosis in fibroblasts, led us to hypothesise that Alix may have such a role at the presynapse. The present study has allowed us to demonstrate that Alix concentrates at presynaptic boutons during intense stimulation. Using mutant forms of Alix, we demonstrate that this recruitment of Alix is depends on the ability of Alix to interact with the calcium binding protein, ALG-2. Endophilin-A is also recruited to presynaptic boutons and this recruitment is dependent on its capacity to interact with Alix. It is then revealed that the lack of Alix in neurons leads to impaired ADBE, suggesting the importance of Alix in ADBE. Such a role of Alix depends on its ability to interact with ALG-2 and endophilin since the impairment of ADBE was reversed upon rescuing the expression of wild-type Alix, but not with Alix mutants unable interact with ALG-2 or endophilin-A.The findings of this study demonstrate that Alix is important for clathrin-independent endocytosis at synapses, a process necessary for the recycling of synaptic vesicles during normal neuronal activity.
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Kwangil Chi. Role of Alix in endocytosis at presynaptic boutons. Neurons and Cognition [q-bio.NC]. Université Grenoble Alpes, 2019. English. ⟨NNT : 2019GREAV001⟩. ⟨tel-02185968⟩

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