Deciphering the molecular mechanisms of neuronal development deficits in Prader-Willi syndrome: insights into hypothalamic dysfunction

Funding Summary

By creating three-dimensional hypothalamic organoids from hiPSCs with PWS-relevant deletions, Dr. Tai will investigate how specific genetic changes drive molecular and cellular alterations in PWS. The study will identify disease-relevant genes, pathways, and cell types, establishing a framework for future research that includes rescuing molecular and cellular phenotypes in these models through targeted interventions.

Lay Abstract

Prader-Willi syndrome (PWS) is primarily caused by paternal deletions on chromosome 15q11.2-q13, with two common deletion types: Type I (6 Mb) and Type II (5.3 Mb). Individuals with PWS often suffer from hypothalamic dysfunction, leading to symptoms such as excessive eating, obesity, and fertility issues. Our research aims to model these genetic deletions at a cellular level using human induced pluripotent stem cells (hiPSCs) and advanced CRISPR techniques. Hypothalamic dysfunction is a hallmark of PWS, and understanding its underlying molecular and cellular mechanisms is essential for therapeutic development. By creating three-dimensional hypothalamic organoids—lab-grown miniatures of the hypothalamus—from hiPSCs with PWS-relevant deletions, we can investigate how specific genetic changes drive molecular and cellular alterations in PWS. This approach has the potential to reveal how hypothalamic disruptions contribute to the symptoms of PWS and to identify key disease-related networks as possible therapeutic targets. Our study will identify disease-relevant genes, pathways, and cell types, establishing a framework for future research that includes rescuing molecular and cellular phenotypes in these models through targeted interventions. This project lays the groundwork for potential therapeutic development for PWS by uncovering key molecular and cellular changes linked to hypothalamic dysfunction. Insights from these organoid models could be instrumental in creating mechanism-based treatments or clinical interventions to improve the quality of life for individuals with PWS.