ERATO Mizushima Intracellular Degradation Project & IRCN Joint Seminar
"Phase Separation at the Nerve Terminal"
|Date and Time||Monday, July 8, 2019 14:00~15:00|
|Venue|| Seminar Room #1&2
@ 2F, Faculty of Medicine Experimental Research Building
|Speaker||Dr. Dragomir Milovanovic
Departments of Neuroscience and Cell Biology, Program in Cellular Neuroscience, Neurodegeneration and Repair, Kavli Institute for Neuroscience, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA
|Seminar flyer||PDF 207KB|
Neuronal transmission relies on the sustained release of neurotransmitters from synaptic vesicles (SVs) upon depolarization of neurons. Nerve terminals contain hundreds of SVs that form tight clusters. Despite being held together, vesicles are highly mobile within these clusters, so that they can be randomly recruited to the surface of the cell to release their content upon activation of the neuron. How this compact, yet the dynamic organization is achieved remained elusive. Several studies in the past decade showed that macromolecules may assemble into distinct liquid compartments not-limited by a membrane, a process known as liquid-liquid phase separation.
Recently we have discussed (Milovanovic and De Camilli, Neuron, 2017) how several features of SV clusters suggest that they may be part of a distinct liquid phase in the cytosol. For example, SV clusters have sharp boundaries, exclude other organelles, vesicles in these clusters are mobile, and SVs can be exchanged with vesicles outside the cluster. Thus, SV cluster may represent a distinct liquid phase in which one component of the phase are synaptic vesicles and the other component are proteins of the intervening matrix.
In our latest study, we show that synapsin 1, a highly abundant synaptic protein, forms a distinct liquid phase in an aqueous environment. Synapsin 1 exchanges readily between the phase where is enriched and the surrounding medium. Additional synapsin 1 binding scaffolding proteins further modulate this phase but are not necessary for its formation. Importantly, synapsin 1 can capture small lipid vesicles into its phase. The phase of synapsin 1 rapidly disassembles upon phosphorylation by CaMKII, mimicking the dispersion of synapsin 1 that occurs at presynaptic boutons upon simulation. Thus, a minimal system of synapsin (with or without its binding partners) may sequester lipid vesicles, forming a distinct liquid phase.
Synapsin 1 contains a large amino acid sequence at its C terminal that does not fold into any stable secondary or tertiary structure, so-called intrinsically disordered region (IDR). The hallmark of many neurodegenerative diseases is misfolding and aggregation of proteins with IDRs. Hence, it is of key importance to understanding how these proteins underlie the spatial organization and solubility necessary for functionality in the crowded environment of the nerve terminal.
- Milovanovic D and De Camilli P. Synaptic vesicle clusters at synapses: a distinct liquid phase? (2017) Neuron, 93: 995
- Milovanovic D, Wu Y, Bian X, De Camilli P. A liquid phase of synapsin and lipid vesicles. (2018) Science, 361: 604
For more information
Seiichi Koike <firstname.lastname@example.org> （Ext. 21414）
Mizushima Laboratory, Department of Biochemistry and Molecular Biology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo