Histones facilitate ?-synuclein aggregation during neuronal apoptosis.

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

SUBMITTER: Jiang P 

PROVIDER: S-EPMC5350017 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature