Projects Archive - Foundation for Prader-Willi Research | Neurobiology

The focus of our proposal is to unravel the complexities of developmental and hormone-responsive dysfunction within human hypothalamic circuits in Prader-Willi Syndrome using cutting edge human brain circuits within a petri dish using organoids.

Dr. Azevedo is interested in a particular set of neurons (the lateral septum, LS, neurons) in the brain that express the PWS-region gene, MAGEL2, since these neurons may be important in controlling feeding behavior. Here, she will investigate whether LS neurons behave differently in PWS mice compared to ‘wild-type mice’, potentially identifying a...

Dr. Carmichael has been investigating the changes in gene expression of PWS cells lacking SNORD116 genes compared to typical cells and has identified a set of 40 genes that are differentially expressed. In year 2 they will further characterize these genes and their role in PWS and will examine how SNORD116 controls their expression.

Dr. Yosten is using a combined spatial imaging approach to perform a detailed analysis of the proteins and genes found in hypothalamus of individuals with PWS, in comparison to typical individuals. They will build a data-sharing platform that can be used by the entire scientific community to analyze gene and protein differences in PWS brain...

Dr. Ross has been investigating a particular region of the brain (medial prefrontal cortex) and class of neurons in PWS mice, to understand their link to cognitive and metabolic changes in PWS. They will determine whether stimulating these neural circuits in the brains of PWS mice reduces food intake and improves learning, potentially identifying...

Dr. Reiter has used stem cells derived from baby teeth to look at differences in how PWS neurons in a dish develop compared to typical neurons. He has found changes in circadian rhythm and timing of development. Year 2 work will focus on ‘rescuing’ these characteristics by delivering different PWS-region genes to the cells.

This renewal application builds on excellent work to date from the Friedman lab, which has identified a new subset of neurons in the hypothalamus and a novel gene that may be driving hyperphagia in PWS. They will explore how Magel2 impacts the function in these neurons and whether a pharmacological approach can impact their newly identified...

Dr. Laugsch's group will examine the normal function of the MAGEL2 protein compared to MAGEL2 harboring SYS mutations, analyzing neuronal growth and function in the laboratory dish.

Through previous work using a new optimized method, Dr. Whipple discovered that Snord116, a driver of PWS, directly interacts with ribosomes, the machinery that produces proteins in the cell in mouse neurons. In this funded project, they will apply their optimized method to human neurons to ask if the interaction between SNORD116 and ribosomes is...

Working with the Autism BrainNet, Dr. Yeo and his team will examine hypothalamic tissue samples from six individuals with PWS. The research team apply cutting edge molecular analysis to these precious samples and to map the architecture of the PWS hypothalamus, providing insight into the changes underlying appetite control. They will create a...

These researchers hypothesize that PWS is associated with changes in the perception of food odors, which may drive some aspects of hyperphagia. In this study, Drs. Steculorum and Tauber will examine the role of olfaction in both patients with PWS and a mouse model of PWS, and will explore how one potential treatment, oxytocin, impacts the...

People with PWS have abnormally high amounts of REM sleep and inappropriate occurrence of REM sleep in the middle of active wake periods. A specific population of neurons in the lateral hypothalamus secretes a neuroactive substance called melanin-concentrating hormone (MCH), which control REM sleep. To determine if MCH neurons are overactive in...

Dr. Fon Tacer’s studies will provide mechanistic insights into how loss of the PWS-region gene, MAGEL2, results in deficits of secretory granules (SG), which are essential for the proper release of hormones from cells. Such an understanding is critical for determining how to restore neuroendocrine function for therapeutic purposes. This project...

Our recent research identified a new brain pathway, the cerebellum-ventral striatum circuit, in regulating appetite and satiation. In the proposed study, we plan to test whether safe, non-invasive modulation of this circuit, using a technique called transcranial magnetic stimulation (TMS), can impact the function of this circuit and reduce food...

One effect of the lack of Magel2 in PWS is lower production of a brain neurotransmitter called orexin. Orexin is key to regulating a number of physiological processes, including hunger and physical activity, and we hypothesize that the obesity and related metabolic function symptoms seen in PWS is linked to a reduction in the levels of orexin in...

Data from the first year of this project that in the postnatal period mice that lack Snord116 (Snord116del) have dramatic changes in neuronal morphology in both the cortex and hippocampus, brain regions that are essential for cognitive function. In the second phase of this project, we will characterize the electrical activity and functional...

Dr. Ross will investigate how feeding behavior and cognitive flexibility are jointly regulated in the prefrontal cortex of the brain, in neurons expressing MC4R. This study may define a neuronal circuit to target therapeutically.

In this project Dr. Lodato will use stem cells from PWS patients to generate human 3D cortical organoids (a ‘minibrain in a dish’). Human cortical organoids are valuable models that mimic aspects of human brain development, and analysis of these organoids is expected to shed light on how brain development in PWS differs from that in typical...

Dr. Reiter’s previous studies suggest that PWS neurons exhibit delayed maturation compared to neurons from typical individuals. Here, his team will use RNA sequencing during neuronal differentiation to better understand the molecular basis of the developmental delay and identify new targets for therapeutic interventions. His team will also...

Prader-Willi (PWS) and Schaaf-Yang syndromes (SYS) are disorders that are both caused by alterations of the MAGEL2 gene, which is either completely missing (PWS) or non-functional (SYS). Working with PWS and SYS mouse models, Dr. Schaaf will investigate the function of a brain ‘support cell’ (astrocytes), which have recently been found to be...

Preliminary research done by Dr. Grzechnik has shown that “long non-coding RNAs”, (lncRNAs) from PWS-region genes may act as important regulators in neurodevelopment. In this project, Dr. Grzechnik will study the changes that occur when the PWS lncRNAs are depleted during the early, middle and late stages of neuronal development.

A protein called CART controls appetite and body weight in both lean and obese rodents and mutations in the CART gene have been linked to obesity in humans. The protein GPR160 helps CART signal brain cells to control appetite. However, CART and GPR160 have not been studied in PWS before. Therefore, this project will evaluate the role of CART in...

The cognitive challenges experienced by many individuals with PWS remains poorly understood. Pilot data obtained in the Wells laboratory indicates that loss of expression of PWS-region gene, Snord116, leads to reduced length and branching of a certain type of neuron in the cortex of the brain. In this project they will use specialized techniques...

The goal of the second year of this research project is to determine, using a preclinical mouse model of PWS, when do the maximal health and biological effects of oxytocin occur (birth, infancy, puberty, or adult life). The study also examines neurological mechanisms by which oxytocin treatment exerts its effects on feeding and behavior in PWS....

Dr. Dietrich’s lab has been working on “hunger” neurons, Agrp neurons, that are contained in the hypothalamus in animal brains. They have found that PWS-related genes, particularly Magel2, are enriched in Agrp neurons. In the second year of funding for this study, they will use a mouse model that is missing Magel2 to look at the function of the...

The role of the brain in controlling food intake is increasingly apparent, with studies finding that genes related to obesity often play a role in brain regions crucial for feeding, appetite, and satiety. Prader-Willi syndrome, one of the most common forms of genetic obesity, results increased food intake (hyperphagia) leading to severe obesity,...

Prader-Willi Syndrome (PWS) is a genetic condition resulting from paternal inheritance of a deletion within an imprinted region of chromosome 15q. The smallest known deleted region encompasses a small nucleolar non-coding RNA locus called SNORD116 (SNORD116), but very little is known about how deletion of SNORD116 leads to PWS. As shown using...

There is currently no cure for Prader-Willi syndrome (PWS). PWS is a complex and debilitating disorder that significantly impacts the lives of not only affected patients, but their families, as well. Recent work has revealed a genetic basis for PWS, and a number of the genes affected are known to have unique expression patterns throughout the...

There are two goals to this study: 1) To identify differences between individuals with PWS with autism from those who have PWS without autism using technology that analyzes how genes are expressed and 2) To identify a new role for SNORD115 and SNORD116 which may help explain the PWS condition or how other very small molecules that do not make...

Although PWS is best known for hypothalamic obesity and hyperphagia, the cognitive and behavioral issues are the most challenging for families. Previous neuroanatomical studies in PWS have examined cells in the hypothalamus. To date, no data are available on the cellular structure of the brain in PWS in the frontal lobe where executive function...

Caregivers, physicians and patients with PWS report that daytime sleepiness in PWS significantly disrupts daily life. However, the underlying cause of excessive daytime sleepiness in PWS is unknown. Dr. Scammell’s group is exploring the contribution of reduced neuronal function in the hypothalamus region of the brain, specifically, oxytocin/orexin...

Through a normal biological process called genomic imprinting, the chromosome 15 that is inherited from the father has a set of genes that are switched on while the same set of genes on the chromosome 15 inherited from the mother are switched off. In Prader-Willi syndrome (PWS), there is no normal copy of the paternal chromosome 15 so patients...

Although PWS is best known for hypothalamic obesity and hyperphagia, the cognitive and behavioral issues are the most challenging for families. Brain difference is the underpinning of the characteristics that define the Prader-Willi personality: food related behaviors, excessive/repetitive behaviors, stress sensitivity/mood disorder, cognitive...

A hallmark symptom of PWS is extreme, unrelenting hyperphagia associated with obesity. Other medical characteristics of individuals with PWS include low circulating growth hormone, short stature, adrenal insufficiency, hypothyroidism, and hypogonadism. Additionally, individuals with PWS have decreased levels of circulating fasting insulin compared...

Recent technological developments have ushered in a new era for the medical research field based on our ability to generate stem cells (called induced pluripotent stem cells or iPSCs) out of adult patient cells, such as blood or skin fibroblasts. There are two important benefits of this technology relevant for research into Prader Willi Syndrome...

Study one: There is a reduction in the number of neurons that produce oxytocin in people with PWS. This, along with a range of other evidence supports the likelihood that abnormalities in the oxytocin system are key to the problems of PWS. However, studies examining the levels of oxytocin in PWS as well as clinical trials evaluating the effect...

Prader-Willi Syndrome (PWS) is a rare genetic disorder with symptoms that typically include obesity, severe appetite and impaired reproductive function. It is thought that dysfunction of the hypothalamus, a part of the brain that controls body weight and reproduction, underlies some of these symptoms. Our goal is to understand what is...

The loss of two regulatory RNAs is critical for the development of Prader-Willi syndrome. One of these RNAs prevents the formation of a truncated serotonin receptor. We will test the role of this truncated serotonin receptor in the production of growth hormones and determine whether it is a 'master regulator' for other receptors. Based on our...

Through a normal biological process called genomic imprinting, the chromosome 15 that is inherited from the father has a set of genes that are switched on while the same set of genes on the chromosome 15 inherited from the mother are switched off. In Prader-Willi syndrome (PWS), there is no normal copy of the paternal chromosome 15 so patients...

Background: MAGEL-2 is a gene frequently deleted or mutated in individuals affected with PWS. Furthermore, mice lacking MAGEL-2 display symptoms similar to those seen in PWS children. However, a critical barrier to our understanding of MAGEL-2’s link to PWS has been determining its function within cells. Recently, my group has solved this...

Many individuals with PWS have sleepiness, abnormal rapid eye movement (REM) sleep, and falling episodes resembling cataplexy - episodes of muscle paralysis that are usually triggered by strong, positive emotions. Caregivers, physicians and patients with PWS report significant disruption of daily life as a result of these sleep-related symptoms....

Prader-Willi syndrome (PWS) is a genetic disease characterized by an insatiable appetite and a variety or behavioral dysregulations. It is known that the brain, and particularly a region of the brain called the hypothalamus, is important to regulating appetite and body weight. We also know that many key physiological processes, including appetite...

MAGEL2 is one of five genes in the Prader-Willi syndrome (PWS) critical domain on chromosome 15 that encodes a protein. Our group recently described a group of patients with mutations of MAGEL2 causing Prader-Willi features and autism. Autism spectrum disorder is seen in up to one third of individuals with PWS, and in all individuals with MAGEL2...

The MAGEL2 gene appears as one of the main genes involved in feeding and behavioral (autistic like behavior) alterations observed in Prader-Willi Syndrome. We showed that, in mouse, the deficiency of Magel2 results in a phenotype similar to the clinical description of patients with mutations in MAGEL2. Indeed, we showed that Magel2-deficient mice...

The genetic disorder Prader-Willi syndrome (PWS), results in debilitating physical, endocrine, cognitive, and behavioral symptoms. Many of the characteristics of PWS, such as uncontrollable food intake, stunted growth, and emotional problems suggest that disruptions in brain regions such as the hypothalamus may cause this. Recently, the gene...

Prader-Willi Syndrome (PWS) is a rare disorder, sharing common genes with autism and schizophrenia; patients with PWS are at a high risk of developing psychiatric illnesses and behavioral problems, however, the underlying neurobiology that places them at-risk is yet unknown. Here we propose a cross-sectional, multi-faceted brain imaging study in...

Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by lack of inherited genes from fathers on chromosome 15. PWS is characterized by intellectual disabilities, repetitive and compulsive behaviors, social cognition deficits, increased eating and obesity. These individuals typically consume up to three times the normal caloric...

The vagus nerve is a major route of communication between the brain and the gut. Vagus nerve stimulation (VNS) is a procedure whereby a small implanted device placed under the skin on a patient’s chest delivers an intermittent electrical impulse to the vagus nerve, which will travel up and down the nerve and into the brain and to the gut. VNS has...

This supplement will help Dr. M. Tauber complete the study awarded in 2011: Early to midterm oxytocin effects on the brain metabolism of adults with Prader-Willi syndrome. Prader-Willi syndrome (PWS) is a rare multisystem genetic disease leading to severe disabilities such as morbid obesity, as well as behavioral and socialization problems. We are...

Individuals with Prader Willi Syndrome (PWS) are known to display frequent and severe temper outburst behaviours throughout their life. These behaviours can have a significant impact on the quality of life for the individual and their family. Prader Willi outbursts are reactive explosion of emotion that once provoked the individual has little...

Mental illness is a major problem in Prader-Willi syndrome (PWS). It prevents social interactions and seriously threatens the quality of life of the patient and of those around the patient. Mood swings, stereotyped repetitive behaviors, psychotic episodes are dependent on proper functioning of brain regions such as the prefrontal cortex. Activity...

Prader-Willi Syndrome (PWS) is a rare disorder, sharing common genes with autism and schizophrenia; patients with PWS are at very high risk of developing severe psychiatric illnesses and behavioral problems, however, the underlying neurobiology that places them at-risk is yet unknown. Here we propose a cross-sectional, multi-faceted brain imaging...

Among the many complications of Prader-Willi Syndrome (PWS), the increased food intake (hyperphagia) has serious long-term medical consequences. The goal of this proposal is to define novel brain regions that may contribute to this problem. Studies of brain activity suggest that the prefrontal cortex might be different in PWS patients. This is an...

Prader-Willi syndrome (PWS) is a genetic disease characterized by an insatiable appetite and a variety of behavioral dysregulations. It is known that the brain, and particularly a region of the brain called the hypothalamus, is important to regulating appetite and body weight. We also know that many key physiological processes, including appetite...

Prader-Willi syndrome (PWS) is caused by a loss of expression of specific genes normally expressed only from paternal alleles on chromosome 15. PWS patients display common symptoms, which include feeding difficulties in infancy, loss of muscle tone, rapid weight gain after two years of age, extreme hunger and unrelenting appetite, obesity, and...

The brain balances energy stores with energy expenditure with little conscious effort. The hypothalamus is a part of the brain that senses levels of a hormone called leptin, which is produced by fat. Excess leptin normally causes a decrease in appetite and increase in activity. This balance is disrupted in obese children who carry mutations in...

Prader-Willi syndrome (PWS) is a rare multisystem genetic disease leading to severe disabilities such as morbid obesity, as well as behavioral and socialization problems. We are greatly lacking in information on the natural history of this complex disease and the factors involved in its progression and outcome. Early diagnosis and a...

Although the genetic region on chromosome 15 that is responsible for Prader-Willi Syndrome (PWS) has been known for many years, how the gene or genes within this large region cause the complex clinical features of PWS is still unknown. We have identified a small deletion on chromosome 15 of a patient with PWS features that narrows the causative...

Many people with Prader-Willi Syndrome (PWS) frequently engage in severe skin picking behavior, often causing open wounds and sores that can become infected. Why do people with PWS do this? How often and under what circumstances does it occur? Are people with PWS more likely to exhibit skin picking when they are bored or anxious? Does the skin...

Two lines of evidence are promoted this proposal. First, recently, smaller microdeletions in the region between the human SNRPN and UBE3A genes have been reported in several cases with features consistent with PWS, including childhood obesity, hyperphagia, and hypogonadism. Second, interestingly, recent studies of genomewide survey of imprinting...

Prader-Willi syndrome (PWS) is a genetic disorder characterized by impairment of a myriad of physiological systems including growth, development, metabolism and reproduction. Although the physiological deficits observed in individuals with PWS come to be well-recognized, the mechanisms and/or cause for the generation of these characteristics are...

A better understanding of the causes of Prader-Willi syndrome (PWS) and the discovery of potential therapies has been hampered by the unavailability of live tissues. In our laboratory (Marc Lalande), we have established induced pluripotent stem cell (iPSC) technology to create models of human disease in a test tube/tissue culture dish. Skin cells...

Prader-Willi Syndrome (PWS) is a genetic disease characterized by failure to thrive and low muscle tone during infancy, followed by food-seeking and severe obesity in childhood. Other manifestations include altered pain perception, cognitive impairment, maladaptive behaviors (obsessive compulsive, temper tantrums, skin picking, rigid thinking and...

Prader-Willi syndrome (PWS) is a disease caused by mutations on human chromosome 15 leading to "floppy" infants initially, and obesity and sleep disorders later. Although genetic defects underlying PWS have been documented, it is still not well understood how the loss-of-function of genes results in various symptoms in PWS. It has been shown that...

Prader-Willi Syndrome (PWS) is a complex genetic disorder in which several genes are missing or not functional. PWS is characterized by initial loss of muscle tone and failure to thrive neonatally; children with PWS develop behavioral and cognitive problems, reproductive defects, and excessive overeating. A major medical concern is the morbid...

The Prader-Willi syndrome (PWS) is a disease caused by mutations on human chromosome 15 leading to "floppy" infants initially, and obesity and sleep disorders later. Although genetic defects underlying PWS have been documented, it is still not well understood how the loss-of-function of genes results in various symptoms in PWS. It has been shown...

The cause of the severe obesity characteristic of patients with Prader-Willi syndrome (PWS) is unknown. In the past few years however, there has been an explosion of information regarding the factors involved in the control of bodyweight. In particular, the hormone leptin, which is produced by fat, and a group of molecules in the brain called the...

(Year 2 of this project)

In patients suffering Prader-Willi syndrome it has been shown that there is a greatly elevated level of a hormone known as ghrelin. This hormone is known to normally stimulate hunger and food intake. However, the levels of the circulating hormone leptin that signals the need to reduce food intake and increase energy expenditure is not similarly up...

Background The automatic nervous system performs many functions that are abnormal in PWS: feeding, drinking, thermoregulation, intestinal motility, reproduction, reaction to stress and infection and together with the autonomic system of the brain, emotion and other complex behaviors. The cells (neurons) of the autonomic nervous system extend...

Prader-Willi Syndrome is a disorder characterized by numerous medical conditions, including excessive eating, low metabolic rate, growth hormone deficiency, hypogonadism and various cognitive deficits. In fact, obese individuals with PWS are described as having a nearly constant state of hunger, which manifests in various maladaptive feeding...

Prader-Willi syndrome (PWS) is a genetic disorder characterized by a number of clinical features, including short stature, poor muscle development, excessive appetite with progressive obesity, mental retardation, behavioural abnormalities and sleep disturbances. Obesity occurs in over 90% of affected individuals and is the most prominent physical...

Human behavior is determined by the brain. The function of the brain relies on connections between various types of neurons. The main form of communication between neurons is via the so called synapses. The number and type of synapses between neurons are determinants of behavior. Thus, we hypothesize that altered behavior in people with PWS is due...

Background. The autonomic nervous system (ANS) performs functions that are abnormal in PWS: feeding, drinking, thermoregulation, intestinal motility, reproduction, reaction to stress and infection, and together with the ANS of the brain, emotion and other complex behaviors. The cells (neurons) of the ANS communicate with important organs such as...