Other ways to search: Events Calendar | UTHSC

Collaboration Researching Angelman Syndrome Publishes Findings, Receives $2.4 Million Award


A three-way research collaboration at the University of Tennessee Health Science Center (UTSHC) is achieving crucial advances in finding a new target for Angelman syndrome, a rare neurogenetic disorder characterized by intellectual disability, balance issues, motor impairment, and debilitating seizures.

Dr. Julio Cordero-Morales

Julio Cordero-Morales, PhD, and Valeria Vásquez, PhD, both associate professors of Physiology in the UTHSC College of Medicine, have spent years studying the cellular processes of mechanosensation, the conversion of mechanical stimuli into neuronal signals. These complex processes allow us to interpret and navigate the physical world, enabling us to sense our position in space, maintain our balance, and perform coordinated movements like walking.

The mechanosensitive ion channel PIEZO2 is expressed in sensory neurons. It mediates proprioception (the sense that allows us to know where our bodies are in space) and balance. Mice and humans lacking PIEZO2 expression have an unsteady gait, irregular stride and step length, and unstable posture. This phenotype is shared by individuals suffering from Angelman syndrome, which is caused by the loss of UBE3A gene expression in neurons.

The investigators suspected that there could be a connection and teamed up with Lawrence Reiter, PhD, professor in the Department of Neurology. Dr. Reiter has over 20 years of experience in the Angelman syndrome field. The research was led by a graduate student, Luis Romero, and an instructor, Rebeca Caires Mugarra, PhD.

“Together, we provided several lines of evidence demonstrating that PIEZO2 currents are reduced in Ube3a-deficient mouse neurons and stem cell-derived neurons from individuals with Angelman syndrome,” Dr. Cordero-Morales, lead investigator, said. “Our results demonstrate that PIEZO2 is a potential therapeutic target.”

The team used a dietary fatty acid (linoleic acid) to increase PIEZO2 activity, mechano-excitability, and improve gait in a mouse model of Angelman syndrome. Moreover, the investigators demonstrated that linoleic acid supplementation increased PIEZO2 activity in dental pulp stem cell-derived neurons from multiple individuals with Angelman syndrome, part of a patient repository developed by Dr. Retier.

“Our work represents the first example in which a dietary fatty acid intervention has been used to enhance the function of a mechanosensitive sensory ion channel,” Cordero-Morales said. “We revealed that PIEZO2 function is compromised in Angelman syndrome and that PIEZO2 is a potential pharmacological target for the rescue of ataxia in this neurogenetic disorder.”

The project is gaining national recognition and support. The study findings were published in the article “Linoleic acid improves PIEZO2 dysfunction in a mouse model of Angelman Syndrome” in the March 2023 issue of the journal Nature Communications, and the investigators were recently awarded $2.4 million by the National Institute of Neurological Disorders and Stroke.