Synucleins rule the synaptic domain: Evidence from a topographical point of view

Abstract

Vargas KJ, Schrod N, Davis T, et al. Synucleins have multiple effects on presynaptic architecture. Cell Rep 2017;18(1):161-173.Point mutations in a-synuclein can reproduce symptoms resembling sporadic Parkinson's disease in both humans and mice. The strategic distribution of the small-sized ubiquitous alpha, beta, and gamma isoforms of this protein is known to alter synaptic membrane trafficking and interfere with synaptic vesicles' exocytosis. This happens as a result of synuclein's unique ability to induce, detect, and respond to synaptic membrane conformational changes and regulate phospholipase D2 and the amount of SNARE complex in synaptic terminals. 1 Through immunoelectron microscopy and cryoelectron tomography on wild-type, synuclein-null, and overexpressing mutant a-synuclein synaptic terminals, Vargas and colleagues 2 were able to provide novel insights into the crucial architectural alterations in the synaptic terminal and the presynaptic cytomatrix in PD associated with the synuclein molecule. Surprisingly, they revealed that the majority of a-synuclein particles (74.2%) were natively localized on synaptic vesicle membranes rather than the synaptic membrane alone. Synuclein deletion reduced the synaptic span and vesicle size while increasing the density of active zone vesicles. Axial distribution of synaptic vesicles was unaltered and signs of release defect, reduced number of "docked" vesicles (zone 1 from the synaptic surface, 0-45 nm), were not identified in synuclein-null slices compared to the wild type.Furthermore, synuclein-null synapses had more tethers in total and in proximal synaptic vesicles and a significantly shortened length of tethers (<5 nm) in cryoelectron tomography. When addressing changes in the readily releasable pool (RRP) of neurotransmitters in the docked synaptic vesicles of mice, they found that the fraction of multiply tethered synaptic vesicles (RRP) was increased by 3-to 4fold in synuclein-free synapses. Protein linkages between synaptic vesicles that form them into clusters(connectors) were decreased in the proximal and intermediate zone, but not in the distal pool of the synaptosome, where the synaptic vesicle clusters belonged to the RRP pool. Together these denote a distal shift in the active synaptic vesicles pool in abg Syn-null mice, a phenomenon reversed by the introduction of wild-type human a-synuclein.Vargas et al also revealed that the point mutation of PARK1/hA30P increased a-synuclein synaptic expression, induced shorter tethers and more synaptic vesicles aggregated by tethers resembling mirror synuclein-null properties. The PARK4/ha-syn mutation, however, affected the synaptic cytomatrix and interfered with neurotransmitter release. Through this final step they validate their results, underscoring synucleins as crucial players in synaptic pathophysiology in Parkinson's disease from structural and functional standpoints.