Membrane trafficking in neurons regulated by new syntaxin 13-interacting proteins

Recently, it has been shown that correct trafficking of neuronal plasma membrane receptors along the endosomal pathway is directly implicated in molecular mechanisms underlying synaptic plasticity and is fundamental for proper neuronal communication. To understand the molecular mechanisms that regulate neuronal trafficking through endosomes, we used syntaxin 13, an endosomal protein that we had previously characterized, as a bait to immunopurify protein complexes. Among the 5 new syntaxin 13-interacting proteins that we identified, my thesis work has focused on the characterization of 2 of them, Neuron-Enriched Endosomal Protein of 21 kDa (NEEP21) and Reticulon1-C (RTN1-C). NEEP21. Our work revealed that NEEP21 is expressed by neurons in their somatodendritic compartments, where it is mainly found in Rab4-positive subdomains of early endosomes. This domain has been implicated in the sorting of internalized surface receptors. We demonstrated that NEEP21 suppression strongly retards recycling of receptors including AMPA-type glutamate receptors. We recently identified a molecular link between NEEP21 and AMPA-receptor trafficking. NEEP21 is present in a complex with GRIP, a scaffold protein for GluR2, and GluR2, a subunit of AMPA receptors. Overexpression of the NEEP21 binding site for GRIP causes a retraction of dendrites, an effect partially compensated by GluR2 overexpression. In addition, expression of this fragment inhibits AMPA receptor recycling. Based on the recent findings of the importance of AMPA receptor trafficking between endosomes and the cell membrane during synaptic structural and functional plasticity, we postulate that NEEP21 modulates synaptic strength. RTN1-C. The second identified syntaxin 13-associated protein is RTN1-C. Reticulons constitute a family of membrane proteins localized primarily to the endoplasmic reticulum (ER). So far the cellular function of reticulons is little undertsood. We found that RTN1-C interacts with several SNARE proteins. In addition, we showed that overexpression of the RTN1-C binding site for syntaxin 1 significantly enhanced regulated secretion. Based on these findings, we hypothesized that RTN1-C could be a key actor in the regulation of SNARE-dependent membrane fusion processes. Together, our studies contribute to the elucidation of the roles of NEEP21 and RTN1-C in neurons and the molecular mechanisms of membrane protein trafficking that are at fundamental for synaptic plasticity.

    Thèse École polytechnique fédérale de Lausanne EPFL, n° 3091 (2004)
    Faculté des sciences de la vie
    Institut des neurosciences
    Jury: Ruth Luthi-Carter, Antonio Malgaroli, William Pralong, Romano Regazzi

    Public defense: 2004-11-5


    Record created on 2005-03-16, modified on 2016-08-08

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