Linoleic Acid Improves Piezo2 Dysfunction in a Mouse Model of Angelman Syndrome

Authors

Luis O Romero
Rebeca Caires
A Kaitlyn Victor
Juanma Ramirez
Francisco J Sierra-Valdez
Patrick Walsh
Vincent Truong
Jungsoo Lee
Ugo Mayor
Lawrence T Reiter
Valeria Vásquez
Julio F Cordero-Morales

Publication Date

3-1-2023

Journal

Nature Communications

Abstract

Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability and atypical behaviors. AS results from loss of expression of the E3 ubiquitin-protein ligase UBE3A from the maternal allele in neurons. Individuals with AS display impaired coordination, poor balance, and gait ataxia. PIEZO2 is a mechanosensitive ion channel essential for coordination and balance. Here, we report that PIEZO2 activity is reduced in Ube3a deficient male and female mouse sensory neurons, a human Merkel cell carcinoma cell line and female human iPSC-derived sensory neurons with UBE3A knock-down, and de-identified stem cell-derived neurons from individuals with AS. We find that loss of UBE3A decreases actin filaments and reduces PIEZO2 expression and function. A linoleic acid (LA)-enriched diet increases PIEZO2 activity, mechano-excitability, and improves gait in male AS mice. Finally, LA supplementation increases PIEZO2 function in stem cell-derived neurons from individuals with AS. We propose a mechanism whereby loss of UBE3A expression reduces PIEZO2 function and identified a fatty acid that enhances channel activity and ameliorates AS-associated mechano-sensory deficits.

Keywords

Animals, Female, Humans, Male, Mice, Alleles, Angelman Syndrome, Disease Models, Animal, Intellectual Disability, Ion Channels, Linoleic Acid