Monoamine Oxidase-B Inhibition Facilitates -Synuclein Secretion In Vitro and Delays Its Aggregation in rAAV-Based Rat Models of Parkinson's Disease

Cell-to-cell transmission of alpha-synuclein (alpha-syn) pathology is considered to underlie the spread of neurodegeneration in Parkinson's disease (PD). Previous studies have demonstrated that alpha-syn is secreted under physiological conditions in neuronal cell lines and primary neurons. However, the molecular mechanisms that regulate extracellular alpha-syn secretion remain unclear. In this study, we found that inhibition of monoamine oxidase-B (MAO-B) enzymatic activity facilitated alpha-syn secretion in human neuroblastoma SH-SY5Y cells. Both inhibition of MAO-B by selegiline or rasagiline and siRNA-mediated knock-down of MAO-B facilitated alpha-syn secretion. However, TVP-1022, the S-isomer of rasagiline that is 1000 times less active, failed to facilitate alpha-syn secretion. Additionally, the MAO-B inhibition-induced increase in alpha-syn secretion was unaffected by brefeldin A, which inhibits endoplasmic reticulum (ER)/ Golgi transport, but was blocked by probenecid and glyburide, which inhibit ATP-binding cassette (ABC) transporter function. MAOB inhibition preferentially facilitated the secretion of detergent-insoluble alpha-syn protein and decreased its intracellular accumulation under chloroquine-induced lysosomal dysfunction. Moreover, in a rat model (male Sprague Dawley rats) generated by injecting recombinant adeno-associated virus (rAAV)-A53T alpha-syn, subcutaneous administration of selegiline delayed the striatal formation of Ser129-phosphorylated alpha-syn aggregates, and mitigated loss of nigrostriatal dopaminergic neurons. Selegiline also delayed alpha-syn aggregation and dopaminergic neuronal loss in a cell-to-cell transmission rat model (male Sprague Dawley rats) generated by injecting rAAV-wild-type alpha-syn and externally inoculating alpha-syn fibrils into the striatum. These findings suggest that MAO-B inhibition modulates the intracellular clearance of detergent-insoluble alpha-syn via the ABC transporter-mediated non-classical secretion pathway, and temporarily suppresses the formation and transmission of alpha-syn aggregates.