+検索条件
-Structure paper
タイトル | O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology. |
---|---|
ジャーナル・号・ページ | Nat Chem Biol, Vol. 20, Issue 5, Page 646-655, Year 2024 |
掲載日 | 2024年2月12日 |
著者 | Aaron T Balana / Anne-Laure Mahul-Mellier / Binh A Nguyen / Mian Horvath / Afraah Javed / Eldon R Hard / Yllza Jasiqi / Preeti Singh / Shumaila Afrin / Rose Pedretti / Virender Singh / Virginia M-Y Lee / Kelvin C Luk / Lorena Saelices / Hilal A Lashuel / Matthew R Pratt / |
PubMed 要旨 | Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer's and Parkinson's disease, can form different fibril structures or strains with distinct toxic properties, ...Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer's and Parkinson's disease, can form different fibril structures or strains with distinct toxic properties, seeding activities and pathology. Understanding the determinants contributing to the formation of different amyloid features could open new avenues for developing disease-specific diagnostics and therapies. Here we report that O-GlcNAc modification of α-synuclein monomers results in the formation of amyloid fibril with distinct core structure, as revealed by cryogenic electron microscopy, and diminished seeding activity in seeding-based neuronal and rodent models of Parkinson's disease. Although the mechanisms underpinning the seeding neutralization activity of the O-GlcNAc-modified fibrils remain unclear, our in vitro mechanistic studies indicate that heat shock proteins interactions with O-GlcNAc fibril inhibit their seeding activity, suggesting that the O-GlcNAc modification may alter the interactome of the α-synuclein fibrils in ways that lead to reduce seeding activity in vivo. Our results show that posttranslational modifications, such as O-GlcNAc modification, of α-synuclein are key determinants of α-synuclein amyloid strains and pathogenicity. |
リンク | Nat Chem Biol / PubMed:38347213 / PubMed Central |
手法 | EM (らせん対称) |
解像度 | 4.8 Å |
構造データ | EMDB-29980, PDB-8gf7: |
化合物 | ChemComp-NAG: |
由来 |
|
キーワード | PROTEIN FIBRIL / alpha-synuclein / O-GlcNAc / amyloid / fibril / posttranslational modification |