γ-Synuclein: Seeding of α-Synuclein Aggregation and Transmission between Cells

Protein misfolding and aggregation is a ubiquitous phenomenon associated with a wide range of diseases. The synuclein family comprises three small naturally unfolded proteins implicated in neurodegenerative diseases and some forms of cancer. alpha-Synuclein is a soluble protein that forms toxic inclusions associated with Parkinson's disease and several other synucleinopathies. However, the triggers inducing its conversion into noxious species are elusive. Here we show that another member of the family, gamma-synuclein, can be easily oxidized and form annular oligomers that accumulate in cells in the form of deposits. Importantly, oxidized gamma-synuclein can initiate alpha-synuclein aggregation. Two amino acid residues in gamma-synuclein, methionine and tyrosine located in neighboring positions (Met(38) and Tyr(39)), are most easily oxidized. Their oxidation plays a key role in the ability of gamma-synuclein to aggregate and seed the aggregation of alpha-synuclein. gamma-Synuclein secreted from neuronal cells into conditioned medium in the form of exosomes can be transmitted to glial cells and cause the aggregation of intracellular proteins. Our data suggest that post-translationally modified gamma-synuclein possesses prion-like properties and may induce a cascade of events leading to synucleinopathies.