Neuron Specific Rab4 Effector GRASP-1 Coordinates Membrane Specialization and Maturation of Recycling Endosomes

The neuronal protein GRASP-1 is shown to be a key molecule controlling endosomal trafficking and thereby regulating synapse integrity and synaptic plasticity.
The endosomal pathway in neuronal dendrites is essential for membrane receptor trafficking and proper synaptic function and plasticity. However, the molecular mechanisms that organize specific endocytic trafficking routes are poorly understood. Here, we identify GRIP-associated protein-1 (GRASP-1) as a neuron-specific effector of Rab4 and key component of the molecular machinery that coordinates recycling endosome maturation in dendrites. We show that GRASP-1 is necessary for AMPA receptor recycling, maintenance of spine morphology, and synaptic plasticity. At the molecular level, GRASP-1 segregates Rab4 from EEA1/Neep21/Rab5-positive early endosomal membranes and coordinates the coupling to Rab11-labelled recycling endosomes by interacting with the endosomal SNARE syntaxin 13. We propose that GRASP-1 connects early and late recycling endosomal compartments by forming a molecular bridge between Rab-specific membrane domains and the endosomal SNARE machinery. The data uncover a new mechanism to achieve specificity and directionality in neuronal membrane receptor trafficking.
Author Summary Neurons communicate with each other through specialized structures called synapses, and proper synapse function is fundamental for information processing and memory storage. The endosomal membrane trafficking pathway is crucial for the structure and function of synapses; however, the components of the neuronal endosomal transport machinery are poorly characterized. In this paper, we report that a protein called GRASP-1 is required for neurotransmitter receptor recycling through endosomes and back to the cell surface, as well as for the normal morphology of dendritic spines—the projections that form synapses—and for synaptic plasticity. We show that GRASP-1 coordinates coupling between early and later steps of the endocytic recycling pathway by binding to Rab4, a regulator of early endosomes, and to another endosomal protein found later in the pathway called syntaxin 13—a so-called SNARE protein involved in membrane fusion. GRASP-1 binds Rab4 with its N terminus and syntaxin 13 with its C terminus, suggesting that these interactions could structurally and functionally link early endosomes to those later in the recycling pathway. We propose a model in which GRASP-1 forms a molecular bridge between different endosomal membranes and the SNARE fusion machinery. Our study thus provides new mechanistic information about endosome function in neurons and highlights GRASP-1 as a key molecule that controls membrane receptor sorting and recycling during synaptic plasticity.