Magel2 deficiency drives microglial synaptic engulfment and alters neuron-microglia interactions in Prader-Willi syndrome
- 1Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
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.
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BibTeX
@misc{helen2026magel2,
title = {{Magel2 deficiency drives microglial synaptic engulfment and alters neuron-microglia interactions in Prader-Willi syndrome}},
author = {J. Helen and M. C. Wimmer and B. Kanmaz and T. Schubert and I. P. Paranhos and F. Correa-da-Silva and Y. Podpecan and A. J. Muhammad and E. M. Eisemann and N. Illma and D. S. Arslan and M. Iminitoff and F. Schommer and H. Froehlich and F. Franke and Z. Gu and D. Huebschmann and M. E. Blewitt and H. Yu and M. J. Low and V. Vogel and D. Kazdal and E. G. Bochukova and M. K. Kirchner and T. Gruber and I. S. Farooqi and F. Muscatelli and D. Swaab and C.-X. Yi and H. L. Tan and F. Althammer},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.30.755583},
url = {https://www.biorxiv.org/content/10.64898/2026.09.30.755583v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Magel2 deficiency drives microglial synaptic engulfment and alters neuron-microglia interactions in Prader-Willi syndrome
AU - J. Helen
AU - M. C. Wimmer
AU - B. Kanmaz
AU - T. Schubert
AU - I. P. Paranhos
AU - F. Correa-da-Silva
AU - Y. Podpecan
AU - A. J. Muhammad
AU - E. M. Eisemann
AU - N. Illma
AU - D. S. Arslan
AU - M. Iminitoff
AU - F. Schommer
AU - H. Froehlich
AU - F. Franke
AU - Z. Gu
AU - D. Huebschmann
AU - M. E. Blewitt
AU - H. Yu
AU - M. J. Low
AU - V. Vogel
AU - D. Kazdal
AU - E. G. Bochukova
AU - M. K. Kirchner
AU - T. Gruber
AU - I. S. Farooqi
AU - F. Muscatelli
AU - D. Swaab
AU - C.-X. Yi
AU - H. L. Tan
AU - F. Althammer
PY - 2026
DA - 2026/09/30
PB - bioRxiv
DO - 10.64898/2026.09.30.755583
UR - https://www.biorxiv.org/content/10.64898/2026.09.30.755583v1
AB - 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.
ER -