Adenosine Receptor Functionality and Desensitization Machinery in a Neuronal Cell Model of Angelman Syndrome

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Angelman syndrome (AS) is a neurodevelopmental disorder resulting from the loss of maternal UBE3A gene expression.
• This loss disrupts proteostasis and synaptic function, impacting neuronal development.
• Adenosine receptors (ARs) are crucial G protein-coupled receptors regulating neuronal differentiation and outgrowth.

Purpose of the Study:

• To investigate adenosine receptor (AR) signaling in a cellular model of Angelman syndrome (AS).
• To determine the influence of AR signaling on survival-autophagy balance and neuronal morphology in AS.
• To explore the role of UBE3A in regulating AR expression, desensitization, and downstream signaling pathways.

Main Methods:

• Utilized SH-SY5Y cells with silenced UBE3A to model Angelman syndrome (AS).
• Assessed protein levels of adenosine receptors (ARs) and G protein-coupled receptor kinase 2 (GRK2).
• Analyzed ligand affinity, receptor desensitization kinetics, GRK2 recruitment, and downstream effects on MDM2-p53 axis and autophagy markers.

Main Results:

• UBE3A deficiency altered AR expression, notably decreasing A1AR, A2BAR, and A3AR while increasing A2AAR.
• AR desensitization kinetics were slower in UBE3A-deficient cells, linked to altered GRK2 dynamics.
• AR agonists promoted survival, modulated the MDM2-p53 axis and autophagy, and increased neurite density in AS cells.

Conclusions:

• Angelman syndrome (AS) is characterized by altered adenosine receptor (AR) levels and impaired desensitization mechanisms.
• AR signaling modulation impacts proteostasis, autophagy, and neuronal morphology in AS.
• These findings highlight ARs as potential therapeutic targets for Angelman syndrome (AS).