From dark coat to neurodegeneration: Functional analysis of attractin and mahogunin.

摘要

Abstract: Agouti protein is a paracrine signaling molecule that induces yellow pigment production by antagonizing melanocortin-1 receptor (Mc1r). Attractin (Atrn) and mahoganoid (Mgrn1) are closely related coat color mutations that suppress the effects of Agouti on pigmentation. Using both genetics and biochemistry, I found that Atrn encodes a type I transmembrane protein that serves as a low-affinity accessory receptor for Agouti protein, and Mgrn1 encodes a widely expressed intracellular RING-class E3 ubiquitin ligase that is required to down-regulate Mc1r signaling. Surprisingly, Atrn and Mgrn1 both have a broader expression pattern and greater evolutionary conservation compared with Agouti. Insight into this apparent paradox comes from a detailed histological survey of Atrn and mahoganoid mutant mice, in which we found neurodegeneration characterized by spongiform changes, age-dependent progression and reactive astrocytosis. The neuropathological features of both mutants greatly resemble those of prion disease, but their molecular pathogenesis is independent of PrP. These findings suggest that Atrn and Mgrn1 are closely linked components of an ubiquitin-dependent pathway that regulates both neuronal viability in the brain and pigment-type switching in the skin.