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

Area of Science:

• Neurogenetics
• Molecular Neuroscience
• Cellular Physiology

Background:

• Angelman syndrome (AS) is a neurogenetic disorder caused by the loss of UBE3A maternal allele expression in neurons.
• AS is associated with intellectual disability, atypical behaviors, impaired coordination, poor balance, and gait ataxia.
• PIEZO2, a mechanosensitive ion channel, is crucial for maintaining coordination and balance.

Purpose of the Study:

• To investigate the impact of UBE3A loss on PIEZO2 function in Angelman syndrome.
• To explore the potential of linoleic acid (LA) as a therapeutic agent for AS-associated motor deficits.

Main Methods:

• Assessed PIEZO2 activity in sensory neurons from Ube3a-deficient mice, human cell lines, and iPSC-derived neurons from AS individuals.
• Examined the effects of UBE3A loss on actin filaments and PIEZO2 expression.
• Investigated the impact of a linoleic acid-enriched diet and LA supplementation on PIEZO2 function and gait in AS mice and neurons.

Main Results:

• PIEZO2 activity was reduced in Ube3a-deficient neurons across various models.
• Loss of UBE3A led to decreased actin filaments, reduced PIEZO2 expression, and impaired function.
• Linoleic acid (LA) supplementation enhanced PIEZO2 activity, mechano-excitability, and improved gait in AS mice and neurons.

Conclusions:

• Loss of UBE3A expression in Angelman syndrome impairs PIEZO2 channel function.
• Linoleic acid shows promise in ameliorating AS-associated mechano-sensory deficits by enhancing PIEZO2 activity.
• This study identifies a potential therapeutic strategy targeting fatty acid metabolism for Angelman syndrome.