This project aims to clarify the role of the brain’s cholinergic system in PWS and its connection to cognitive difficulties and hyperphagia. Dr. Yi and her team hypothesize that acetylecholine (ACh) deficiency in the brains of individuals with PWS may contribute to their cognitive impairments and appetite-related challenges, as the cholinergic system relies on ACh, a neurotransmitter crucial for brain functions like learning, memory, attention, mood, and sleep regulation. Building on these findings, this research project will investigate ACh levels in living individuals with PWS and their relationship to symptom severity using non-invasive PET imaging and blood tests. Additionally, Dr. Yi will explore potential reasons for ACh deficiency by analyzing the genetic and molecular characteristics of brain cells in PWS, aiming to identify pathways involved in ACh production and guide future treatment development.
Lay Abstract
This research focuses on understanding the neurological basis of Prader-Willi Syndrome (PWS), a complex genetic disorder that presents with a range of symptoms, including insatiable hunger (hyperphagia) leading to overeating and obesity, endocrine (hormonal) deficiencies, and cognitive impairments affecting learning, memory, mood and attention. Despite ongoing research, the neurological underpinnings of these symptoms remain only partially understood. This project aims to clarify the role of the brain’s cholinergic system in PWS and its connection to cognitive difficulties and hyperphagia.
The cholinergic system relies on acetylcholine (ACh), a neurotransmitter crucial for brain functions such as learning, memory, attention, mood, and sleep regulation. ACh also plays a key role in activating hypothalamic neurons, which help regulate appetite. Our analysis of postmortem brain tissue from individuals with PWS revealed a significant reduction in neurons expressing choline acetyltransferase (ChAT), the enzyme that synthesizes ACh. We hypothesize that ACh deficiency in the brains of individuals with PWS may contribute to their cognitive impairments and appetite-related challenges.
Building on these findings, this research project will investigate ACh levels in living individuals with PWS and their relationship to symptom severity. Using non-invasive PET imaging and blood tests, we will measure ACh levels in the brain and circulation and assess their correlation with cognitive and behavioral symptoms. Additionally, we will explore potential reasons for ACh deficiency by analyzing the genetic and molecular characteristics of brain cells in PWS, aiming to identify pathways involved in ACh production and guide future treatment development.
In the short term, the study could provide solid evidence that enhancing ACh levels may alleviate cognitive and behavioral symptoms in PWS. If successful, drugs known as AChE inhibitors, already under investigation for Alzheimer’s disease, could potentially be repurposed to improve cognition and control hunger in individuals with PWS. Over the longer term, these findings could enable the development of targeted treatments that address the root causes of ACh deficiency. As individuals with PWS are living longer, these treatments could help delay or prevent age-related cognitive decline, including dementia, in this population.
This project directly advances the development of PWS therapies by identifying cholinergic system as a treatment target, establishing non-invasive measures for ACh levels, and testing potential treatments. Through clarifying ACh’s role in PWS, this research provides a foundation for new therapies to alleviate cognitive impairments and hyperphagia, ultimately improving the quality of life and clinical care for individuals with PWS.