C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Alpha-synuclein (α-syn) is a protein implicated in neurodegenerative diseases.
• α-syn is known to interact with lipid membranes, particularly small unilamellar vesicles (SUVs), through its N-terminus.

Purpose of the Study:

• To investigate the role of calcium in the interaction of α-syn with synaptic vesicles.
• To elucidate the binding regions of α-syn on synaptic vesicles and how calcium influences this interaction.

Main Methods:

• Chemical Exchange Saturation Transfer Nuclear Magnetic Resonance (CEST-NMR) to study α-syn interaction with isolated synaptic vesicles.
• Direct Stochastic Optical Reconstruction Microscopy (dSTORM) on synaptosomes to visualize α-syn localization.
• Ex vivo and in vitro experiments to observe synaptic vesicle clustering.

Main Results:

• Calcium binding to the C-terminus of α-syn increases its lipid-binding capacity.
• α-syn interacts with synaptic vesicles via both its N-terminus and C-terminus, with C-terminal interaction regulated by calcium.
• Calcium mediates the localization of α-syn to the pre-synaptic terminal.
• Imbalances in calcium or α-syn levels lead to synaptic vesicle clustering.

Conclusions:

• Calcium plays a crucial role in modulating α-syn binding to synaptic vesicles.
• The dual-region interaction of α-syn with synaptic vesicles, regulated by calcium, provides a new perspective on synaptic function.
• Understanding this mechanism may offer insights into the pathogenesis of synucleinopathies.