Serine-129 phosphorylation of α-synuclein is an activity-dependent trigger for physiologic protein-protein...

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Phosphorylation of alpha-synuclein (α-syn) at serine-129 (Ser129) is a hallmark of synucleinopathies.
• Existing research primarily focuses on the pathological implications of α-syn Ser129P.
• The physiological role and regulation of α-syn Ser129P remain underexplored.

Purpose of the Study:

• To investigate the intrinsic regulation and functional significance of α-syn Ser129P in physiological conditions.
• To elucidate the mechanisms by which neuronal activity influences α-syn Ser129P.
• To explore the structural consequences of Ser129 phosphorylation on α-syn interactions.

Main Methods:

• Comparative analysis of wild-type α-syn and α-syn Ser129P expression patterns.
• Functional assays examining the impact of preventing Ser129 phosphorylation on synaptic function.
• Biochemical experiments to identify activity-dependent regulation of Ser129 phosphorylation.
• Computational modeling (AlphaFold2) and membrane-binding simulations.

Main Results:

• α-syn Ser129P exhibits a restricted expression pattern distinct from widely expressed wild-type α-syn.
• Inhibition of Ser129 phosphorylation impairs activity-dependent synaptic attenuation mediated by α-syn.
• Neuronal activity enhances α-syn Ser129P, triggering protein-protein interactions essential for synaptic function.
• Ser129 phosphorylation induces conformational changes facilitating α-syn binding partner interactions.

Conclusions:

• α-syn Ser129 phosphorylation is crucial for normal α-syn function at the synapse, particularly in response to neuronal activity.
• This modification regulates synaptic plasticity and protein interactions, challenging the view of Ser129P as solely pathological.
• Findings provide a new framework for understanding synucleinopathies and developing targeted therapeutics.