Ample in vitro and in vivo experimental evidence supports the hypothesis that intercellular transmission of alpha-synuclein (alpha S) is a mechanism underlying the spread of alpha S pathology in Parkinson's disease and related disorders. What remains unexplained is where and how initial transmissible alpha S aggregates form. In a previous study, we demonstrated that alpha S aggregates rapidly form in neurons with impaired nuclear membrane integrity due to the interaction between nuclear proaggregant factor(s) and alpha S and that such aggregates may serve as a source for alpha S seeding. In the present study, we identify histones as a potential nuclear proaggregant factor for alpha S aggregation in both apoptotic neurons and brains with alpha S pathology. We further demonstrate that histone-induced aggregates contain a range of alpha S oligomers, including protofibrils and mature fibrils, and that these alpha S aggregates can seed additional aggregation. Importantly, we demonstrate transmissibility in mouse brains from stereotaxic injection. This study provides new clues to the mechanism underlying initial pathological aggregation of alpha S in PD and related disorders, and could lead to novel diagnostic and therapeutic approaches.