Cellular Signatures of Melanocortin Pathway Genes Across the Locus Coeruleus [Spatial Transcriptomics]

The melanocortin pathway gene MRAP2 was expressed in the majority of DBH neurons across the LC. Mrap2 was also co-expressed with AD-associated genes such as App, Psen1, Psen2, and Sorl1. More than 20% of Dbh neurons in the LC were positive for Mrap2, App, Psen1, and Psen2.

Mrap2 is expressed in the central nervous system and modulates the trafficking and signaling of all five G-protein coupled receptors (GPCRs) of the melanocortin receptor family: Mc1r, Mc2r, Mc3r, Mc4r, and Mc5r. In mice, among the melanocortin receptors, Mc5r showed the highest co-expression with Mrap2, accounting for 17.9% of Mrap2-positive cells, followed by Mc2r with 10.9% of Mrap2-positive cells. Mc1r, Mc3r, and Mc4r showed very limited co-expression with Mrap2.

Our study reveals that many Mrap2-positive cells do not express any melanocortin receptor genes, warranting future studies into metabolically relevant GPCRs downstream of MRAP2 in the LC. In summary, our study characterizes melanocortin molecular substrates in the human and mouse LC and highlights MRAP2 as a potential link between pathways of energy homeostasis and neurodegeneration.