Saturday, December 21, 2024
12/21/2024
PROJECT SUMMARY/ABSTRACT Phosphoinositide signaling lipids are key regulators of endomembrane trafficking and are critical for synaptic function and plasticity. Notably, many synapse-specific trafficking pathways are highly similar to cognate pathways in non-neuronal cells. The specialized trafficking at synapses is largely achieved via modest alterations to generic trafficking pathways. Due to the high demand of traffic at synapses, very minor mutations in these pathways specifically impact the nervous system and underlie a wide range of neurological disorders. PIKfyve and its regulatory proteins Vac14 and Fig4 control the cellular levels of the low abundance signaling lipids phosphatidylinositol (3,5)-bis phosphate (PI3,5P2) and phosphatidylinositol 5- phosphate (PI5P). Studies from us and others revealed that minor mutations in this pathway are associated with several neurological disorders. Insights into roles of PI(3,5)P2 in neurons came from our discovery that PIKfyve plays essential roles in synaptic function and plasticity, and acts in part via controlling the surface levels of AMPA- type glutamate receptors (AMPARs). PIKfyve downregulation results in enhanced recycling and surface levels of AMPAR, although the underlying molecular mechanism(s) are unknown. Paradoxically, our new studies in non-neuronal cells, reveal that PIKfyve has a direct positive role in the control of the SNX17 recycling pathway. Notably, both the SNX17 and SNX27 pathways emerge from the same microdomains on endosomes. This places PIKfyve on endosomes that actively recycle both SNX17-dependent and SNX27-dependent cargoes. Importantly AMPAR surface levels are controlled in part via SNX27-dependent recycling. Aim 1 of this proposal seeks to determine whether PIKfyve controls AMPAR surface levels via negative regulation of SNX27- dependent recycling. Importantly, our new studies raise the possibility that dysregulation of SNX17 during PIKfyve inhibition, may also contribute to the observed synaptic defects. Mutations in proteins that function with SNX17 underlie some neurological diseases, but surprisingly, there are no published studies to establish whether SNX17 recycling is critical for synaptic function. The current project will test the hypothesis that PIKfyve differentially regulates distinct recycling pathways that emerge from the same endosomes. To address this hypothesis we will 1) Determine mechanisms whereby PIKfyve regulates AMPAR recycling; 2) Determine roles of the SNX17- Retriever pathway in neurons and whether similar to non-neuronal cells, PIKfyve is a regulator of this pathway.
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