Sigma-2 Receptor Antagonists Rescue Neuronal Dysfunction Induced By Parkinson'S Patient Brain-Derived Alpha-Synuclein

alpha-Synuclein oligomers are thought to have a pivotal role in sporadic and familial Parkinson's disease (PD) and related alpha-synucleinopathies, causing dysregulation of protein trafficking, autophagy/lysosomal function, and protein clearance, as well as synaptic function impairment underlying motor and cognitive symptoms of PD. Moreover, trans-synaptic spread of alpha-synuclein oligomers is hypothesized to mediate disease progression. Therapeutic approaches that effectively block alpha-synuclein oligomer-induced pathogenesis are urgently needed. Here, we show for the first time that alpha-synuclein species isolated from human PD patient brain and recombinant alpha-synuclein oligomers caused similar deficits in lipid vesicle trafficking rates in cultured rat neurons and glia, while alpha-synuclein species isolated from non-PD human control brain samples did not. Recombinant alpha-synuclein oligomers also increased neuronal expression of lysosomal-associated membrane protein-2A (LAMP-2A), the lysosomal receptor that has a critical role in chaperone-mediated autophagy. Unbiased screening of several small molecule libraries (including the NIH Clinical Collection) identified sigma-2 receptor antagonists as the most effective at blocking alpha-synuclein oligomer-induced trafficking deficits and LAMP-2A upregulation in a dose-dependent manner. These results indicate that antagonists of the sigma-2 receptor complex may alleviate alpha-synuclein oligomer-induced neurotoxicity and are a novel therapeutic approach for disease modification in PD and related alpha-synucleinopathies.