Felipe Correa da Silva

Guest Speaker: Felipe Correa da Silva

Host: Susanne la Fleur

Amsterdam UMC, Department of Endocrinology and Metabolism & NIN.
Title: Microglial phagolysosome dysfunction and altered neural communication amplify phenotypic severity in Prader-Willi Syndrome with larger deletion.

Abstract:

Prader-Willi Syndrome (PWS) is a rare genetic disorder resulting from a deletion in chromosome 15. Approximately 70% PWS cases involve paternal deletion, with type I (T1) carrying four additional haploinsufficient genes as compared to type II (T2). Notably, individuals with PWS T1 exhibit more pronounced physiological and cognitive abnormalities compared to PWS T2, but the precise neuropathological mechanisms underpinning these differences remain elusive. In this study, using postmortem hypothalamic tissues and structural magnetic resonance images (MRI) obtained from PWS individuals with T1 or T2 deletion, we conducted transcriptomic analyses, profiled cell type specific protein expression in the white matter, neurons, and glial cells and evaluated volumetric parameters of the hypothalamus. We found in the PWS T1 a significant down-regulation of pathways related to cell structure, integrity and neuronal communication compared to PWS T2. We discovered that these changes in PWS T1 are associated with an unusual cytoplasmic fragmentation and defective phagolysosome activity in microglial cells, whereas microglia in PWS T2 appeared morphologically intact but exhibited inflammatory changes. We confirmed that the microglial defect in PWS T1 was likely due to the Cyfip1 gene haploinsufficiency. Furthermore, we observed an increased aquaporin 4 expression in PWS T1, as a potential response to microglial dysfunction and impaired microenvironment homeostasis. Interestingly, structural analysis of structural MRI scannings revealed no alterations in hypothalamic volume in PWS compared to matched controls, irrespective of the subgenotype. Next, we evaluated myelinated tracts and syntactic markers to understand hypothalamic neuronal connectivity in the context of PWS. PWS T1 brains revealed impairment of myelin integrity in the fornix and a lack of synaptophysin expression in the hypothalamus, indicating disruptions in neuronal pathways that govern cognition and memory. Our findings underscore the significance of microglial phagolysosome dysfunction and altered neural communication as pivotal contributors to the phenotypic severity observed in PWS T1.