S resulting from synaptic dysfunction and avoid the spread of oligomer-induced pathology throughout disease progression. Our objective was to recognize anti–synuclein oligomer drug candidates by screening compounds for the ability to rescue -synuclein oligomer-induced deficits in the target population: major neurons. We identified recombinant full-length -synuclein protein oligomer preparations suitable for screening compound libraries that replicate the toxic effects of Parkinson’s patient brain-derived oligomers, employing assays that measure two important elements of cellular function recognized to become disrupted by -synuclein oligomers: intracellular lipid vesicle trafficking (Izzo, ATR Species Staniszewski, et al., 2014) and chaperone-mediated autophagy. Remedy of mature principal hippocampal/cortical neuronal and glial cultures (21 days in vitro; DIV) with recombinant -synuclein oligomers also as -synuclein oligomer species isolated from brain samples from men and women with PD, but not non-PD agematched manage people, resulted in lipid vesicle trafficking deficits. Remedy of neuronal cultures with recombinant -synuclein oligomers also upregulated the expression of lysosomal-associated membrane protein-2A (LAMP-2A), a protein critically expected for chaperone-mediated autophagy. This can be the very first report demonstrating that recombinant -synuclein oligomers have a similar functional influence as PD patient brain-derived -synuclein oligomers. We then screened quite a few libraries of little molecule compounds, which includes the NIH Clinical Collection to identify compounds capable of blocking recombinant -synuclein oligomer-induced lipid vesicle trafficking deficits. Unexpectedly, essentially the most efficient compounds were selective Cereblon Storage & Stability sigma-2 receptor allosteric antagonists, which blocked these deficits within a dose-dependent manner. These compounds also blocked recombinant -synuclein oligomer-induced LAMP-2A upregulation. Molecular interactions among sigma-2 receptor element proteins progesterone receptor membrane component 1(PGRMC1) and transmembrane protein 97 (TMEM97), -synuclein, and proteins that handle vesicular tracking and autophagy (for instance LC3B) may type the basis for these observations. Importantly, and for the first time, these data indicate that small molecule selective sigma-2 receptor complex antagonists can influence a essential modulator in the -synuclein signalingSignificanceOligomeric -synuclein proteins found in Parkinson’s disease patient brain tissue result in neuron dysfunction, and therapeutic approaches efficiently targeting them are urgently necessary. For the first time, this study demonstrates that recombinant and Parkinson’s patient-derived -synuclein result in related lipid vesicle trafficking deficits in neurons, whilst -synuclein species isolated from non-Parkinson’s human control brain samples do not. -Synuclein oligomers also upregulate lysosomal-associated membrane protein-2A (LAMP-2A), a protein essential to chaperonemediated autophagy. A broad search of current drug candidates revealed that antagonists with the sigma-2 receptor complicated have been essentially the most successful at blocking -synuclein oligomer-induced trafficking deficits and LAMP-2A upregulation. These drug candidates may possibly represent a novel therapeutic approach against Parkinson’s neuronal dysfunction and neurodegenerative problems brought on by -synuclein oligomer-mediated toxicity.LIMEGROVER Et aL.|cascade and cease oligomer-induced deficits. Inhibitors that modulate sigma-2 receptors can be therapeutic against ol.