N-terminal Acetylation Enhances α-Synuclein's Ability to Cluster Synaptic Vesicles by Promoting Interaction with Lysophosphatidylcholine

Core Concepts

N-terminal acetylation of α-synuclein significantly enhances its ability to cluster synaptic vesicles, mediated by increased binding affinity to the neutral lipid lysophosphatidylcholine.

Abstract

This study investigates how post-translational modification of α-synuclein, specifically N-terminal acetylation, impacts its physiological function in synaptic vesicle (SV) clustering. The authors demonstrate that N-acetylation of α-synuclein considerably amplifies its capacity to cluster SVs, which requires the N-terminal 30 residues of the protein.
Mechanistic analyses reveal that N-acetylation significantly enhances the binding affinity of α-synuclein's N-terminal region to the neutral lipid lysophosphatidylcholine (LPC), while modestly reducing its affinity for the negatively charged lipid phosphatidylserine. The increased α-synuclein-LPC interaction promoted by N-acetylation leads to higher intermolecular interactions between α-synuclein monomers, which is crucial for its SV clustering function. In contrast, N-acetylation does not increase α-synuclein's binding to phosphatidylserine, and the electrostatic interaction with this anionic lipid limits intermolecular interactions.
The authors also demonstrate that all unmodified α-synuclein becomes N-terminally acetylated upon expression in mammalian cells, highlighting the physiological relevance of this modification. Overall, this study reveals that N-acetylation fine-tunes the interaction between α-synuclein and lipids, particularly LPC, to optimize α-synuclein's function in SV clustering.

Stats

N-terminal acetylation significantly enhances α-synuclein's ability to cluster synaptic vesicles compared to unmodified α-synuclein.
N-terminal acetylation significantly boosts the clustering ability of α-synuclein with LPC-containing liposomes, but does not increase the clustering of liposomes containing phosphatidylserine.
The number of cross-linked peptide pairs detected in LPC-induced α-synuclein multimers is over twice more than that of phosphatidylserine, indicating higher intermolecular interactions between N-acetylated α-synuclein and LPC.

Quotes

"N-acetylation significantly amplified α-syn's capacity to cluster SVs, which requires the N-terminal 30 residues."
"N-acetylation considerably boosted the clustering ability of α-syn with LPC-containing liposomes, but did not increase the clustering of liposomes containing phosphatidylserine."
"The number of cross-linked peptide pairs detected in LPC-induced α-synuclein multimers was over twice more than that of phosphatidylserine."

Key Insights Distilled From

N-acetylation of α-synuclein enhances synaptic vesicle clustering mediated by α-synuclein and lysophosphatidylcholine

by Wang,C., Zha... at www.biorxiv.org 03-08-2024

https://www.biorxiv.org/content/10.1101/2024.03.04.583437v1

Deeper Inquiries

How might the enhanced α-synuclein-LPC interaction mediated by N-acetylation impact synaptic function and neurotransmitter release under physiological conditions?

The enhanced interaction between α-synuclein and lysophosphatidylcholine (LPC) mediated by N-acetylation can have significant implications for synaptic function and neurotransmitter release. α-synuclein is a key presynaptic protein involved in synaptic vesicle clustering and neurotransmitter release. The increased binding affinity of N-acetylated α-synuclein to LPC can lead to more efficient clustering of synaptic vesicles, which is essential for the regulated release of neurotransmitters. This enhanced interaction may promote the assembly of the soluble N-ethylmaleimide sensitive factor receptor (SNARE) complex, facilitating synaptic vesicle trafficking and neurotransmitter release. Overall, the N-acetylation-induced augmentation of α-synuclein-LPC interaction can fine-tune the protein's function in synaptic vesicle dynamics, ultimately impacting neurotransmission under physiological conditions.

What are the potential implications of the reduced α-synuclein binding to phosphatidylserine upon N-acetylation, and how could this affect synaptic vesicle dynamics and trafficking?

The reduced binding of N-acetylated α-synuclein to phosphatidylserine (PS) can have several implications for synaptic vesicle dynamics and trafficking. Phosphatidylserine is an anionic phospholipid present in synaptic vesicles, and its interaction with α-synuclein is crucial for regulating vesicle clustering and trafficking. The decreased affinity of N-acetylated α-synuclein for PS may alter the protein's localization and function at the presynaptic terminal. This could lead to disruptions in synaptic vesicle clustering and impair the assembly of the SNARE complex, affecting neurotransmitter release. Additionally, changes in α-synuclein-PS binding may impact the overall membrane curvature and lipid packing at the synaptic vesicle membrane, further influencing vesicle dynamics and neurotransmission.

Given the importance of lipid composition in regulating α-synuclein function, how might age-related changes in brain lipid profiles influence α-synuclein's physiological roles and contribute to the pathogenesis of neurodegenerative diseases?

Age-related changes in brain lipid profiles can significantly influence α-synuclein's physiological roles and contribute to the pathogenesis of neurodegenerative diseases. Alterations in lipid composition, such as changes in the levels of LPC, DOPS, and other phospholipids, can impact the interactions of α-synuclein with synaptic vesicles and membranes. These changes may affect the protein's ability to cluster synaptic vesicles, regulate neurotransmitter release, and maintain synaptic function. Moreover, age-related modifications in lipid profiles can lead to disruptions in α-synuclein aggregation and deposition, contributing to the formation of Lewy bodies and the progression of neurodegenerative diseases like Parkinson's disease. Understanding the interplay between age-related lipid changes and α-synuclein function is crucial for elucidating the pathogenic mechanisms underlying neurodegenerative disorders.