Neurodegenerative Disease Related Proteins Have Negative Effects on SNARE-Mediated Membrane Fusion in Pathological Confirmation

Studies showed that synapses are highly-specialized structures for the communication between pre-and postsynaptic neurons (Kaeser and Regehr, 2014). Synaptic vesicles carrying neurotransmitters dock at specialized sites of presynaptic membranes termed active zones, which are closely apposed to postsynaptic densities, and then undergo one or more priming reactions to prepare them to a release-ready state. When an action potential invades the nerve terminals, the following membrane depolarization activates voltage-gated calcium channels to influx Ca 2+ , thus initiates the fusion of synaptic vesicles with presynaptic membrane and transmitters release (Wu and Saggau, 1997). It was reported that synaptic vesicle fusion requires assembly of a conserved proteins family termed soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) (Chernomordik and Kozlov, 2008; Wickner and Schekman, 2008). All SNAREs contain an evolutionarily conserved coiled-coil SNARE motif of ∼60–70 amino acids that are arranged in heptad repeats. In synapses, syntaxin and synaptosome-associated protein of 25 kDa (SNAP-25, contains two SNARE motifs) on the plasma membrane (t-SNAREs on target membrane) and synaptobrevin/vesicle-associated membrane protein (VAMP) on synaptic vesicles (v-SNARE) assemble into a tight trans-SNARE complex in a 1:1:1 ratio to bridge synaptic vesicles and the plasma membrane (Brunger, 2005). The trans-SNARE complex promotes membrane fusion by pulling the bilayers together as it zippers up, and the remaining SNARE complexes on the fused membrane are transformed to cis-configuration with lower potential energy, which undergoes disassembly catalyzed by a specialized adenosine triphosphatase (ATPase) N-ethylmaleimide-sensitive factor (NSF) and its cofactors soluble NSF attachment proteins (SNAPs) (Jahn et al., 2003). SNAPs bind directly to the SNARE complex, then recruit and activate NSF to completely dissociate SNARE complex and recycle individual SNAREs for a new round of fusion reactions (Sudhof and Rothman, 2009). Thus, it appears that the cycle of SNARE assembly and disassembly is critical for the occurrence, the fidelity and plasticity of synaptic transmission. Meanwhile, it has been shown that a wide range of neurodegenerative disorders are characterized with neuronal dysfunction and neuron loss, which caused by the aggregation of specific neurotoxic proteins (Caughey and Lansbury, 2003). Typically, α-synuclein (α-syn), constitutes the amyloid fibril form of Lewy bodies (Wang et al., 2016), is a cytosolic neural protein consisting of 140 amino acid residues and is abundantly expressed in presynaptic membrane in monomeric form (Burre et al., 2013). α-syn is closely associated with early-onset of neurodegenerative diseases prominently in familial Parkinson's disease, Alzheimer's disease and Lewy body disease. Aβ, a peptide …