Magel2 deficiency drives microglial synaptic engulfment and alters neuron-microglia interactions in Prader-Willi syndrome
Year: 2026
Type: preprint
Abstract: Prader–Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hypothalamic dysfunction, developmental delay, hyperphagia, and cognitive impairment, yet the cellular mechanisms underlying circuit abnormalities remain unclear. Here, we show that loss of the imprinted gene Magel2 remodels microglial state and function in a mouse model of PWS. Three-dimensional morphometric analysis of hypothalamic microglia revealed reduced structural complexity and contracted territorial domains, emerging early in development and largely independent of obesity. Single-nucleus RNA sequencing of hypothalamic brain tissue identified extensive transcriptional reprogramming involving immune signaling, cellular communication, ribosome function, synaptic organization, and protein translation, with stronger effects in females. Magel2 deficiency also increased microglia-neuron contacts and synaptic engulfment, accompanied by reduced synaptic marker density, suggesting aberrant refinement of hypothalamic circuits. Analyses of human post-mortem hypothalamic tissue from individuals with PWS confirmed microglial structural alterations and increased complement engagement. Ligand-receptor inference further revealed reorganization of microglia-centered communication networks, including altered adhesion, trophic, and immune signaling consistent with enhanced phagocytic states. Together, these findings identify microglial remodeling and increased synaptic engagement as central features of Magel2 deficiency, implicate microglia in hypothalamic circuit dysfunction in PWS, and highlight excessive synaptic pruning as a novel dysfunctional mechanism of PWS.
Authors: Jemima Helen, Moritz C. Wimmer, Berkan Kanmaz, Tim Schubert, Ingrid Possa Paranhos, Felipe Correa-da-Silva, Yuval Podpecan, Aliyu Jabir Muhammad, Eva M. Eisemann, Nadia Illma, Derya S. Arslan, Megan Iminitoff, Franziska Schommer, Henning Fröhlich, Felix Franke, Zuguang Gu, Daniel Hübschmann, Marnie E. Blewitt, Hui Yu, Malcolm J. Low, Vanessa Vogel, Daniel Kazdal, Elena G. Bochukova, Matthew K. Kirchner, Tim Gruber, I. Sadaf Farooqi, Francoise Muscatelli, Dick Swaab, Chun-Xia Yi, Han L. Tan, Ferdinand Althammer
Institutions: University Hospital Heidelberg, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Howard Hughes Medical Institute, Rockefeller University, The University of Melbourne, Walter and Eliza Hall Institute of Medical Research, Shenzhen University of Advanced Technology, German Cancer Research Center, National Center for Tumor Diseases, The Ohio State University, University of Michigan, Michigan Medicine, German Center for Lung Research, Queen Mary University of London, Blizard Institute, Texas A&M University, University of Cambridge, Helmholtz Munich, National Institute for Health and Care Research, Addenbrooke's Hospital, German Center for Diabetes Research, NIHR Cambridge Biomedical Research Centre, Inserm, Aix-Marseille Université, Institut de Neurobiologie de la Méditerranée, University of California, Irvine
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7215113009