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

Area of Science:

• Neuroscience
• Biochemistry
• Cell Biology

Background:

• Cell-to-cell transfer of alpha-synuclein (αS) is implicated in αS pathology propagation.
• Mechanisms of initial αS seed formation and propagation factors are unclear.
• Histones, released during apoptosis, may promote intracellular αS aggregation.

Purpose of the Study:

• To investigate the role of histones in initiating αS aggregation.
• To determine if histone amyloid fibrils can induce αS pathology.
• To elucidate the cellular mechanisms involved in histone-induced αS aggregation.

Main Methods:

• Utilized mCherry-tagged histone to track histone uptake.
• Prepared nuclear extracts from apoptotic and non-apoptotic cells.
• Induced αS aggregation in cellular and animal models using recombinant histone amyloid fibrils.
• Assessed lysosomal integrity and membrane defects.

Main Results:

• Nuclear extracts from apoptotic cells, but not non-apoptotic cells, induced intracellular αS inclusions.
• Apoptotic nuclear extracts contained histone-immunoreactive amyloid fibrils.
• Histone amyloid fibrils induced αS aggregation in cellular and animal models.
• Histone fibril-induced αS aggregation involved lysosomal rupture, exacerbated by lysosomal defects.

Conclusions:

• Histone amyloid fibrils contribute to the initiation and propagation of αS aggregation.
• Histones released from stressed or apoptotic cells act as potent inducers of αS seeding.
• Lysosomal integrity is crucial in mitigating histone-induced αS pathology.