Journal
HUMAN MOLECULAR GENETICS
Volume 26, Issue 21, Pages 4215-4230Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddx311
Keywords
-
Funding
- Canadian Institutes of Health Research [MOP 130367]
- European Research Council Advanced Grant [340941]
- Faculty of Medicine and Dentistry, University of Alberta
- NSERC Canada Graduate Scholarships-Master's Program
- Stollery Children's Hospital Foundation through a Women and Children's Health Research Institute Graduate Studentship
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available