Building better screens and identifying ligands for human MS4A proteins

In the nose, a family of proteins called the MS4As act as small molecule detectors. These receptors detect ethologically relevant molecules from the environment, including nitrogenous heterocyclics and long chain fatty acids. The MS4As have been strongly implicated by human genetic studies in the development of Alzheimer’s Disease, although the mechanism through which the MS4As are linked to disease are completely unknown. The MS4As are expressed within microglia, a chemosensory cell type within the brain that have been associated with AD progression. We hypothesize that the ability of the MS4As to detect endogenous ligands found in the brain might mediate neuroinflammation associated with AD; if true, this suggests that the MS4As might define a completely new molecular mechanism underlying the AD progression. However, a major challenge in de-orphanizing the MS4As and in identifying chemical activators and inhibitors is the poor behavior of these receptors when expressed on their own in typical reconstitution systems like HEK cells. With support from Q-FASTR, we screened through a variety of cell lines and tested several chaperone candidates, in an attempt to convert our single cell screen for MS4A-dependent responses into a platform useful for high-throughput screening. This work continues, in the hope that identified ligands will be important starting templates for the development of molecules that manipulate MS4A activity, which may have significant therapeutic potential for treating AD.