O-linked N-acetylglucosamine (O-GlcNAc) is an endogenous form of glycosylation that alters the structure of α-synuclein amyloid fibrils and attenuates their pathogenetic properties. The modified fibrils have a significantly reduced ability to seed the aggregation of endogenous α-synuclein in cultured neurons and in mice brains in vivo, which results in reduced pathology.
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References
Eisenberg, D. & Jucker, M. The amyloid state of proteins in human diseases. Cell 148, 1188–1203 (2012). A review article on the fundamentals of amyloid fibril formation and pathogenesis.
Volpicelli-Daley, L. & Brundin, P. Prion-like propagation of pathology in Parkinson disease. Handb. Clin. Neurol. 153, 321–335 (2018). A review article on the evidence for progressive neurodegeneration by α-synuclein seeding mechanisms.
Ma, J., Wu, C. & Hart, G. W. Analytical and biochemical perspectives of protein O-GlcNAcylation. Chem. Rev. 121, 1513–1581 (2021). A review article on the biology of the O-GlcNAc modification.
Balana, A. T. & Pratt, M. R. Mechanistic roles for altered O-GlcNAcylation in neurodegenerative disorders. Biochem. J. 478, 2733–2758 (2021). A review article on the roles of O-GlcNAc in neurodegenerative diseases, including Parkinson’s disease.
Permanne, B. et al. O-GlcNAcase inhibitor ASN90 is a multimodal drug candidate for tau and α-synuclein proteinopathies. ACS Chem. Neurosci. 13, 1296–1314 (2022). A research paper that shows α-synuclein O-GlcNAc modification levels and reduced pathology after a drug-induced increase in O-GlcNAc.
Levine, P. M. et al. α-Synuclein O-GlcNAcylation alters aggregation and toxicity, revealing certain residues as potential inhibitors of Parkinson’s disease. Proc. Natl Acad. Sci. 116, 201808845 (2019). A research paper that demonstrates inhibition of α-synuclein fibrilization by O-GlcNAc.
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This is a summary of: Balana, A. T. et al. O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology. Nat. Chem. Biol. https://doi.org/10.1038/s41589-024-01551-2 (2024).
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Post-translational glycosylation diminishes α-synuclein pathology formation. Nat Chem Biol 20, 553–554 (2024). https://doi.org/10.1038/s41589-024-01553-0
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DOI: https://doi.org/10.1038/s41589-024-01553-0
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