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Corrêa-da-Silva, F.* ; Carter, J.* ; Wang, X.Y.* ; Sun, R.* ; Pathak, E. ; Monroy Kuhn, J.M. ; Schriever, S.C. ; Maya-Monteiro, C.M.* ; Jiao, H.* ; Kalsbeek, M.J.* ; Moraes-Vieira, P.M.M.* ; Gille, J.J.P.* ; Sinnema, M.* ; Stumpel, C.T.R.M.* ; Curfs, L.M.G.* ; Stenvers, D.J.* ; Pfluger, P.T. ; Lutter, D. ; Pereira, A.M.* ; Kalsbeek, A.* ; Fliers, E.* ; Swaab, D.F.* ; Wilkinson, L.* ; Gao, Y.* ; Yi, C.X.*

Microglial phagolysosome dysfunction and altered neural communication amplify phenotypic severity in Prader-Willi Syndrome with larger deletion.

Acta Neuropathol. 147:64 (2024)

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Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of cases. Two distinct genetic subtypes of PWS deletions are characterized, where type I (PWS T1) carries four extra haploinsufficient genes compared to type II (PWS T2). PWS T1 individuals display more pronounced physiological and cognitive abnormalities than PWS T2, yet the exact neuropathological mechanisms behind these differences remain unclear. Our study employed postmortem hypothalamic tissues from PWS T1 and T2 individuals, conducting transcriptomic analyses and cell-specific protein profiling in white matter, neurons, and glial cells to unravel the cellular and molecular basis of phenotypic severity in PWS sub-genotypes. In PWS T1, key pathways for cell structure, integrity, and neuronal communication are notably diminished, while glymphatic system activity is heightened compared to PWS T2. The microglial defect in PWS T1 appears to stem from gene haploinsufficiency, as global and myeloid-specific Cyfip1 haploinsufficiency in murine models demonstrated. Our findings emphasize microglial phagolysosome dysfunction and altered neural communication as crucial contributors to the severity of PWS T1's phenotype.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Fornix ; Glymphatic System ; Hypothalamus ; Immunosurveillance ; Microglia ; Myelin ; Oxytocin; Central-nervous-system; Alzheimer-disease; Myelin; Actin; Hyperphagia; Aquaporin-4; Pathology; Health; Cells

ISSN (print) / ISBN 0001-6322

e-ISSN 1432-0533

Journal Acta Neuropathologica

Quellenangaben Volume: 147, Issue: 1, Article Number: 64

Publisher Springer

Publishing Place One New York Plaza, Suite 4600, New York, Ny, United States

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Obesity (IDO)

Grants Diabetes Fonds
Joris Coppens at the Netherlands Institute for Neuroscience