National Institutes of Health/Office of the Director
OD020103-01
United States
National Institutes of Health/Office of the Director
OD021685-01A1
United States
National Institutes of Health/National Institute on Aging (NIH/NIA)
AG062418
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM114537
United States
Department of Energy (DOE, United States)
DE-AC02-76SF00515
United States
Cancer Prevention and Research Institute of Texas (CPRIT)
RP170644
United States
Citation
Journal: Nat Chem Biol / Year: 2024 Title: O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology. Authors: 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 / ...Authors: 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 / Abstract: 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.
Model: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
Vitrification
Cryogen name: ETHANE / Chamber humidity: 100 %
-
Electron microscopy
Microscope
FEI TITAN KRIOS
Image recording
Film or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 2 / Number real images: 7270 / Average exposure time: 3.6 sec. / Average electron dose: 40.0 e/Å2 / Details: 3 shots per hole
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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