Membraneless compartmentalization of glycolytic proteins to synapses supports synaptic functio

Neurons are highly polarized cells with long extending processes and numerous branches. Scattered throughout the branches and processes are synapses that transmit and mediate informational flow through their activities. Changes in synaptic activity result in local and transient changes in energy demands. Here, I discover that glycolysis is necessary for sustaining synaptic function and synaptic vesicle cycling under acute energy stress in Caenorhabditis elegans neurons. I also identify that glycolytic proteins re-localize from a diffuse localization in the cytoplasm to a punctate localization near synapses in response to energy stress. Several glycolytic enzymes co-localize, suggesting for an assembly of a glycolytic compartment. Disrupting this localization blocks synaptic vesicle cycling, implicating a functional role of this compartment. I further identify that the formation of the glycolytic compartment is reversible in response to energy stress and that these clusters have liquid-like properties. Thus, liquid-liquid phase separation mediates the local and transient formation of the glycolytic compartments at synapses. In summary, my studies uncover glycolysis as a crucial metabolic process in neurons and that this metabolic pathway undergoes dynamic subcellular reorganization via liquid-liquid phase separation in response to energy stress.