title: γ-Synuclein: seeding of α-synuclein aggregation and transmission between cells.
abstract: 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. α-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, γ-synuclein, can be easily oxidized and form annular oligomers that accumulate in cells in the form of deposits. Importantly, oxidized γ-synuclein can initiate α-synuclein aggregation. Two amino acid residues in γ-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 γ-synuclein to aggregate and seed the aggregation of α-synuclein. γ-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 γ-synuclein possesses prion-like properties and may induce a cascade of events leading to synucleinopathies.
authors.affiliation: Veterans Administration Medical Center, Kansas City, MO 66148, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Surgucheva
authors.forename: Victor S
authors.initials: VS
authors.lastname: Sharov
authors.forename: Andrei
authors.initials: A
authors.lastname: Surguchov
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000906:Antibodies; D001253:Astrocytes; D001597:Benzylidene Compounds / Q000494:pharmacology; D002460:Cell Line; D005786:Gene Expression Regulation; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D013058:Mass Spectrometry; D008715:Methionine; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D051381:Rats; D013601:T-Lymphocytes; D051844:alpha-Synuclein / Q000378:metabolism*; D047392:beta-Cyclodextrins / Q000494:pharmacology; D051845:gamma-Synuclein / Q000378:metabolism*
chemical_list: D000814:Aniline Compounds; D000906:Antibodies; D001597:Benzylidene Compounds; C468773:GW 4869; D005904:Glial Fibrillary Acidic Protein; D051844:alpha-Synuclein; D047392:beta-Cyclodextrins; D051845:gamma-Synuclein; C108732:methyl-beta-cyclodextrin; D008715:Methionine