The Prader-Willi syndrome proteins MAGEL2 and necdin regulate leptin receptor cell surface abundance through ubiquitination pathways

Abstract

In Prader-Willi syndrome (PWS), obesity is caused by the disruption of appetite-controlling pathways in the brain. Two PWS candidate genes encode MAGEL2 and necdin, related melanoma antigen proteins that assemble into ubiquitination complexes. Mice lacking Magel2 are obese and lack leptin sensitivity in hypothalamic pro-opiomelanocortin neurons, suggesting dysregulation of leptin receptor (LepR) activity. Hypothalamus from Magel2-null mice had less LepR and altered levels of ubiquitin pathway proteins that regulate LepR processing (Rnf41, Usp8, and Stam1). MAGEL2 increased the cell surface abundance of LepR and decreased their degradation. LepR interacts with necdin, which interacts with MAGEL2, which complexes with RNF41 and USP8. Mutations in the MAGE homology domain of MAGEL2 suppress RNF41 stabilization and prevent the MAGEL2-mediated increase of cell surface LepR. Thus, MAGEL2 and necdin together control LepR sorting and degradation through a dynamic ubiquitin-dependent pathway. Loss of MAGEL2 and necdin may uncouple LepR from ubiquitination pathways, providing a cellular mechanism for obesity in PWS.

A Candidate-Gene Approach Identifies Novel Associations Between Common Variants in/Near Syndromic Obesity Genes and BMI in Pediatric and Adult European Populations

“…Although large deletions involving MRAP2 have been reported in cases of syndromic obesity, pathogenic variants also have been identified in several cases of early onset obesity without additional features (11,31). Moreover, Magel2 (encoded by MAGEL2) promotes the cell surface presence of LepR (32). LepR subsequently interacts with necdin, encoded by NDN (32).…”

“…Moreover, Magel2 (encoded by MAGEL2) promotes the cell surface presence of LepR (32). LepR subsequently interacts with necdin, encoded by NDN (32). POMC neurons in Magel2deficient mice have impaired leptin response, which may be caused by reduced LepR trafficking to the cell surface (33).…”

Endospanin 1 Determines the Balance of Leptin-Regulated Hypothalamic Functions

“…1c). The alteration of the latter by MAGEL2 and necdin mutations is proposed to elicit obesity in patients with Prader-Willi syndrome, characterized by hyperphagia and leptin insensitivity [70]. These mutations appear to alter the sorting and degradation of ObR by a dynamic ubiquitin-dependent pathway, thereby reducing the availability of ObR at the neuronal plasma membrane [70].…”

Choroby rzadkie o podłożu epigenetycznym

“…Na przykład dysfunkcja genów MAGEL2 oraz NDN, kodujących odpowiednio białko Magel2 i nekdynę, jest związana ze skłonnością do oty-łości, gdyż oba białka kontrolują ścieżkę ubikwitynacji i degradacji receptora dla leptyny. Brak Magel2 powoduje spadek poziomu receptora dla leptyny w podwzgórzu, co skutkuje zwiększeniem apetytu [27]. Ogólnie rzecz ujmując nasilenie objawów choroby koreluje z rozmiarem delecji -pacjenci, u których delecji uległ odcinek chromosomu pomiędzy BP1 i BP3 (BP, ang.…”