O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology

Author:

Balana Aaron T.,Mahul-Mellier Anne-Laure,Nguyen Binh A.ORCID,Horvath Mian,Javed Afraah,Hard Eldon R.,Jasiqi Yllza,Singh PreetiORCID,Afrin Shumaila,Pedretti Rose,Singh VirenderORCID,Lee Virginia M.-Y.,Luk Kelvin C.,Saelices LorenaORCID,Lashuel Hilal A.ORCID,Pratt Matthew R.ORCID

Abstract

AbstractAmyloid-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.

Publisher

Springer Science and Business Media LLC

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