VAMP2 chaperones α-synuclein in synaptic vesicle co-condensates

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Alpha-Synuclein (α-Syn) aggregation is a hallmark of Parkinson's disease (PD) neuropathology.
• The physiological role of α-Syn in synaptic vesicle (SV) clustering and SNARE complex assembly is known, but the mechanisms are unclear.
• It remains unknown if α-Syn's physiological function influences its pathological aggregation.

Purpose of the Study:

• To elucidate the structural and molecular mechanisms by which α-Syn functions physiologically.
• To investigate whether α-Syn's physiological function impacts its pathological aggregation.
• To identify the interaction between VAMP2 and α-Syn and its role in regulating α-Syn aggregation.

Main Methods:

• Biochemical assays to study the interaction between VAMP2 and α-Syn.
• Structural analysis to determine the binding interface and mechanism.
• In vitro experiments to assess the effect of VAMP2 binding on α-Syn aggregation and SV clustering.

Main Results:

• The juxtamembrane region of VAMP2 directly interacts with the carboxy-terminal region of α-Syn via charged residues.
• This interaction regulates α-Syn's function in clustering SVs and promoting SNARE complex assembly by inducing a multi-component condensed phase.
• VAMP2 binding protects α-Syn from forming aggregation-prone oligomers and fibrils within these condensates.

Conclusions:

• A molecular mechanism is proposed where VAMP2 binding maintains α-Syn's physiological function.
• This interaction prevents the pathological amyloid aggregation of α-Syn.
• Dysfunction in this mechanism may contribute to the development of Parkinson's disease.