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

Research output: Contribution to journalArticlepeer-review

Abstract

Cell-to-cell transfer of α-synuclein (αS) is increasingly thought to play an important role in propagation of αS pathology, but mechanisms responsible for formation of initial αS seeds and factors facilitating their propagation remain unclear. We previously demonstrated that αS aggregates are formed rapidly in apoptotic neurons and that interaction between cytoplasmic αS and proaggregant nuclear factors generates seed-competent αS. 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 αS expressing cells could lead to intracellular αS aggregation. Here using mCherry-tagged histone, we show that nuclear extracts from apoptotic cells can induce intracellular αS 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 αS aggregation in cellular and animal models. Induction of αS 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 αS aggregation.

Original languageEnglish (US)
JournalMolecular Neurobiology
DOIs
StateAccepted/In press - 2020

Keywords

  • Aggregation
  • Histone
  • Nuclear amyloid fibrils
  • Parkinson’s disease
  • α-Synuclein

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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