Apoptotic Neuron-Derived Histone Amyloid Fibrils Induce α-Synuclein Aggregation

Cell-to-cell transfer of alpha-synuclein (alpha S) is increasingly thought to play an important role in propagation of alpha S pathology, but mechanisms responsible for formation of initial alpha S seeds and factors facilitating their propagation remain unclear. We previously demonstrated that alpha S aggregates are formed rapidly in apoptotic neurons and that interaction between cytoplasmic alpha S and proaggregant nuclear factors generates seed-competent alpha S. We also provided initial evidence that histones have proaggregant properties. Since histones are released from cells undergoing apoptosis or cell stress, we hypothesized that internalization of histones into alpha S expressing cells could lead to intracellular alpha S aggregation. Here using mCherry-tagged histone, we show that nuclear extracts from apoptotic cells can induce intracellular alpha S inclusions after uptake into susceptible cells, while extracts from non-apoptotic cells did not. We also demonstrate that nuclear extracts from apoptotic cells contained histone-immunoreactive amyloid fibrils. Moreover, recombinant histone-derived amyloid fibrils are able to induce alpha S aggregation in cellular and animal models. Induction of alpha S aggregation by histone amyloid fibrils is associated with endocytosis-mediated rupture of lysosomes, and this effect can be enhanced in cells with chemically induced lysosomal membrane defects. These studies provide initial descriptions of the contribution of histone amyloid fibrils to alpha S aggregation.

Automated summary

This study demonstrates that nuclear extracts from apoptotic cells can induce intracellular alpha S aggregation in susceptible cells, suggesting a contribution of histone amyloid fibrils to alpha S aggregation. Additionally, recombinant histone-derived amyloid fibrils are able to induce alpha S aggregation in cellular and animal models, and this effect is associated with lysosome rupture mediated by endocytosis.