Functional and Pathological Effects of α-Synuclein on Synaptic SNARE Complexes

Abstract

α-Synuclein is an abundant protein at the neuronal synapse that has been implicated in Parkinson's disease for over 25 years and characterizes the hallmark pathology of a group of neurodegenerative diseases now known as the synucleinopathies. Physiologically, α-synuclein exists in an equilibrium between a synaptic vesicle membrane-bound α-helical multimer and a cytosolic largely unstructured monomer. Through its membrane-bound state, α-synuclein functions in neurotransmitter release by modulating several steps in the synaptic vesicle cycle, including synaptic vesicle clustering and docking, SNARE complex assembly, and homeostasis of synaptic vesicle pools. These functions have been ascribed to α-synuclein's interactions with the synaptic vesicle SNARE protein VAMP2/synaptobrevin-2, the synaptic vesicle-attached synapsins, and the synaptic vesicle membrane itself. How α-synuclein affects these processes, and whether disease is due to loss-of-function or gain-of-toxic-function of α-synuclein remains unclear. In this review, we provide an in-depth summary of the existing literature, discuss possible reasons for the discrepancies in the field, and propose a working model that reconciles the findings in the literature.

Keywords: Parkinson’s disease; membrane binding; neuronal survival; neurotransmitter release; synaptic vesicle.

Figure 1.

Structure of α-synuclein. The N-terminal domain is comprised of seven imperfect KTKEGV repeats that form two amphipathic α-helices upon binding to synaptic vesicle membranes. This region also contains the aggregation-prone NAC domain, as well as all disease-linked mutations. The C-terminal domain of α-synuclein is not involved in membrane binding and mediates interactions with calcium as well as the SNARE protein VAMP2/synaptobrevin-2.

Figure 2.

Implications of membrane binding of α-synuclein for function and disease. Under physiological conditions, α-synuclein exists in equilibrium between a membrane-bound α-helical conformation on synaptic vesicles and a natively unstructured state in the cytosol. Membrane binding is facilitated by calcium and N-terminal acetylation, whereas the cytosolic pool is increased in presence of β-synuclein or γ-synuclein. α-Synuclein oligomers and fibrils form from the unstructured cytosolic state, leading to neuropathology. Membrane binding of α-synuclein is neuroprotective in its α-helical multimeric state, while association of β-sheet rich oligomeric or fibrillar α-synuclein with synaptic vesicles is linked to neurotoxicity.

Figure 3.

SNARE-dependent effects of α-synuclein on the synaptic vesicle cycle. Upon initiation of an action potential in the presynaptic terminal, synaptic vesicles docked to the plasma membrane fuse to release neurotransmitters to propagate the signal to the next neuron. Synaptic vesicle fusion is mediated by formation of the synaptic SNARE complex, composed of syntaxin-1 and SNAP-25 on the presynaptic plasma membrane, and VAMP2/synaptobrevin-2 on the synaptic vesicle. Following fusion, synaptic vesicle constituents are retrieved via endocytosis. Simultaneous binding of α-synuclein multimers to synaptic vesicle membranes and the synaptic vesicle protein VAMP2/synaptobrevin-2 clusters synaptic vesicles (top inset) and chaperones SNARE complex assembly (bottom inset). In diseased states, pathological α-synuclein or lack of physiologically functional α-synuclein due to recruitment into pathological α-synuclein aggregates results in impaired or dysfunctional synaptic vesicle clustering and reduced SNARE complex assembly. This imbalance in the synaptic vesicle cycle affects long-term neuron function and survival.