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

Journal Article · · Nature Chemical Biology
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  1. University of Southern California, Los Angeles, CA (United States)
  2. École Polytechnique Fédérale de Lausanne (Switzerland)
  3. UT Southwestern Medical Center, Dallas, TX (United States)
  4. University of Pennsylvania, Philadelphia, PA (United States)
+ Show Author Affiliations
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.
Research Organization:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Sponsoring Organization:
USDOE
Grant/Contract Number:
AC02-76SF00515
OSTI ID:
2469854
Journal Information:
Nature Chemical Biology, Journal Name: Nature Chemical Biology Journal Issue: 5 Vol. 20; ISSN 1552-4450
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

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Figures / Tables (14)

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
Biochemistry & Molecular Biology
Glycobiology
Post-translational modifications
Protein aggregation
Proteins