Defective Transferrin Receptor Regulation in the Blood-Brain Barrier Endothelial cells underlies brain iron insufficiency in RLS

This study aims to determine a significant mechanism by which lower iron levels occur in the brain during RLS. In a collaborative project with RLS investigators at Emory University, the researchers found that exposing the cerebrospinal fluid (CSF) of RLS patients disrupts the regulation of transferrin receptors (TfR1), leading to lower iron uptake into the endothelial cells (ECs) of blood vessels of the brain. This proposal focuses on understanding the mechanism underlying this process. The study will interrogate a novel concept that microRNAs (miRNA- small pieces of RNA that can alter proteins being made) will bind to the mRNA of the TfR1 and block the generation of the TfR1 protein.

Dr. Palsa is a Postdoctoral Scholar in the Department of Neurosurgery at Penn State College of Medicine. His research over the past decade has focused on iron homeostasis, with particular emphasis on iron uptake pathways and their regulatory mechanisms from the gut and into the brain. Recently, his research has expanded to include RLS and his work explores that dysregulation of TfR1 expression and EV biogenesis in BBBECs contributes to impaired iron transport into the brain, representing a potential mechanistic basis for iron deficiency in RLS.

Proteomic approach to understanding the mechanism of action for exercise as a non-pharmacological management method in RLS. A pilot study.

This grant was co-funded by the American Academy of Sleep Medicine Foundation

This study employs a two-phase approach to investigate how exercise impacts RLS symptoms and address two key questions:

1. How do RLS symptoms and blood proteins change after a 12-week exercise program?
2. How do RLS symptoms and blood proteins change after a single session of intense exercise?

The significance of this research lies in its potential to elucidate the biological changes that occur with exercise and to develop more personalized treatment strategies for RLS. Understanding these mechanisms will permit targeted selection of exercise parameters (e.g., intensity) to improve symptoms and avoid symptom worsening often seen in RLS.

Dr. Cederberg is currently a Postdoctoral Scholar in the Mignot Lab, where she conducts research aimed at better understanding the relationship among genetics, proteomics, and the presence of and severity of symptoms related to RLS. Her current research interests focus on studying the efficacy and effectiveness of exercise for managing symptoms of RLS and co-occurring conditions (e.g., periodic limb movements, insomnia).

Dr. Mignot is Craig Reynolds Professor of Sleep Medicine at Stanford University. He works on many aspects of sleep research and on unravelling the etiologies of various autoimmune diseases affecting the brain. His approaches are strongly analytic, and include genetics, proteomics, statistics, and deep learning.

Cerebrospinal Fluid Melanocortin and Endorphin in Restless Legs Syndrome Related Augmentation

Dr. Koo was a recipient of the RLS Foundation’s 2024 Research Grant Program, and his study was selected for a second year of funding for 2025. Dr. Koo’s study focuses on studying a family of hormones called the melanocortins and beta-endorphin, based upon their similarity to features of RLS. This study will assess changes in CSF MSH and beta-endorphin in patients with RLS- related augmentation. Levels of CSF MSH and beta-endorphin will be measured during active augmentation and then once again weeks to months later once patients have been successfully taken off dopamine medications and placed onto an alternative agent (e.g. alpha-2-delta ligand or opioid) to treat RLS.

He is currently recruiting applicants for this study across the United States, which requires two visits, the first during active augmentation and the second following proper treatment of augmentation, including tapering off of the dopamine drug. As this study involves CSF, a lumbar puncture will be required at both visits as well as a blood draw. Exclusion criteria include being on an opioid, oral steroid or blood thinning (except aspirin) medication and having diagnoses such as multiple sclerosis, Parkinson’s disease or end stage renal disease. If interested, please contact Emily Rivera at Emily.rivera.er842@yale.edu.

Dr. Koo is an associate professor of neurology at Yale University and the medical director of Sleep Laboratory at the Veterans Affairs Connecticut Healthcare System. His research on RLS and PLMS has included animal modeling, epidemiology, proteomics and genetic analysis.

Involvement of Calcitonin Gene-Related Peptide in Restless Legs Syndrome (RLS): Cerebrospinal Fluid Proteomics Analysis

This project aims to investigate the involvement of calcitonin gene-related peptide (CGRP) in the cerebrospinal fluid of patients with RLS. CGRP is a neuropeptide implicated in pain transmission, inflammatory responses, and the modulation of vascular and sensory functions. By exploring its role in the central nervous system of individuals with RLS, this study seeks to deepen the understanding of the disorder’s underlying mechanisms and contribute to the identification of more precise and targeted therapeutic strategies.

Dr. Mogavero is a neurologist and board-certified sleep medicine specialist at Vita-Salute San Raffaele University in Milan, Italy. She has extensive experience in sleep research, with a particular focus on sleep-related movement disorders. Dr. Mogavero received the Wayne Hening Young Investigator Award from the International Restless Legs Syndrome Study Group (IRLSSG) in both 2022 and 2023, as well as the New Investigator Award from the World Sleep Society in 2023. Her academic roles include faculty appointments in the Level II Master's programs in sleep medicine at the University of Bologna and in clinical sleep medicine at the University of Foggia, as well as teaching at the Catania High School-University of Catania.