Faculty AdvisorPaul Greer
UMass Chan AffiliationsProgram in Molecular Medicine
Document TypeDoctoral Dissertation
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AbstractMutations in MS4A proteins are directly linked to an increased risk for developing neurodegenerative disorders like Alzheimer’s disease. However, neither the native function of these proteins, nor their influence on disease progression is well-understood. Here, we investigated the role of MS4A proteins in mediating Ca2+ signaling and characterized the protein features and conditions that are important for signal transduction. We report that AD-associated MS4A6A is a chemosensor and polymorphisms in the highly conserved amino acids of the transmembrane domains confer null mutants while polymorphisms in the extracellular domains impact ligand specificity. The second extracellular domain of MS4As is necessary and sufficient for ligand-mediated Ca2+ responses and both extracellular and intracellular Ca2+ are necessary for receptor activation. Furthermore, MS4As homo-oligomerize to transduce Ca2+ signals when heterologously expressed in HEK293 cells. Together, these findings significantly advance our understanding of MS4A function and provide insight for potential therapeutic interventions in MS4A-related disease.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/52154
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