Linoleic acid improves PIEZO2 dysfunction in a mouse model of Angelman Syndrome

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 () and Julio F. Cordero-Morales ()
Additional contact information
Luis O. Romero: University of Tennessee Health Science Center
Rebeca Caires: University of Tennessee Health Science Center
A. Kaitlyn Victor: University of Tennessee Health Science Center
Juanma Ramirez: Faculty of Science and Technology, UPV/EHU
Francisco J. Sierra-Valdez: School of Engineering and Sciences, Tecnológico de Monterrey, Ave. Eugenio Garza Sada 2501 Sur
Patrick Walsh: Anatomic Incorporated
Vincent Truong: Anatomic Incorporated
Jungsoo Lee: University of Tennessee Health Science Center
Ugo Mayor: Faculty of Science and Technology, UPV/EHU
Lawrence T. Reiter: University of Tennessee Health Science Center
Valeria Vásquez: University of Tennessee Health Science Center
Julio F. Cordero-Morales: University of Tennessee Health Science Center

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36818-0

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