Dr. Nicholls has identified deficits in a set of proteins that facilitate the folding and maturation of other proteins, ER chaperone proteins. He believes deficits of these proteins in the pancreas is an important contributor to endocrine dysfunction in PWS. Here he will assess the ability of drugs that activate these chaperone proteins to rescue the newborn phenotype in a PWS mouse model.
Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.
Each person with PWS requires lifelong medical care, with major clinical problems affecting behavior, body weight, metabolism, and hormone systems. Hormones provide chemical communication in the body for growth, reproduction, and metabolism including when (hunger) and how much (satiety) we eat and to control blood sugar levels. All are affected in PWS, including reductions in the release of hormones from brain cells (to regulate eating, growth, and reproduction) and from the pancreas (to regulate blood sugar). Growth hormone treatment in PWS improves muscle function, body composition, and height, but is not a cure, with behavioral problems, hyperphagia (constant desire to eat), and low blood sugar (hypoglycemia) unaddressed. The pancreas controls a stable level of blood sugar by regulating release of opposing hormones insulin and glucagon from beta- and alpha-cells, respectively. Our prior work demonstrated that a PWS mouse model has early postnatal lethality due to hypoglycemia, with reduced numbers of hormone-producing cells (known as the islet) and reduced insulin and glucagon; new work with a second PWS mouse model confirms and extends these results. Indeed, episodes of hypoglycemia occur in PWS infants – which can profoundly affect brain development – with anecdotal reports in PWS for all ages and in a pig PWS model. Most recently, we established beta-cell models with the PWS-genetic deletion and found these have a striking defect in release of insulin compared to control beta-cells. Critically, PWS beta-cells had reductions in the protein chaperone machinery that helps hormones traffic out of the cell. Like a personal chaperone to help someone get where they need to go safely, these chaperone proteins make sure that insulin is folded properly and trafficked safely from inside the cell to move outside the cell into the bloodstream. We propose that reduced chaperones result in failure to properly secrete insulin, leading to problems in regulating blood sugar and energy utilization in PWS. The first aim of this study is to assess a novel approach to therapy using non-toxic small molecules to fix the abnormal protein trafficking found in the PWS mouse model beta-cell, rescuing postnatal lethality, islet, and metabolic deficits; preliminary results are promising. This treatment will be provided to the mother during gestation of her litter and as needed after birth. Second, to understand why proteins are not released from cells correctly in PWS, we will examine all single cells that produce different hormones in the PWS mouse model, to identify all gene, protein, and trafficking deficits. An understanding of how hormone release is deficient in PWS will provide a basis for our proposed new therapy for PWS, one that could have profound medical implications.