Authors
Nan Shao, Xiaoyan Zhang, Yunzhi Ge, Jiaxuan Tang, Huawu Gao, Wenwen Si, Biao Cai
Published in
Neural regeneration research. Volume 21. Issue 10. Pages 4715-4728. Oct 01, 2026. Epub Sep 03, 2025.
Abstract
Neurodegenerative disorders are typically caused by harmful protein accumulation and nerve cell damage. A post-translational modification called O-linked N-acetylglucosamine ylation acts as a critical regulator in these disorders by controlling protein behavior, cell signaling, and energy balance. This modification is dynamically balanced through the cooperative actions of O-linked N-acetylglucosamine transferase and O-GlcNAcase. In healthy brains, O-GlcNAcylation supports nerve cell function and survival, but its imbalance contributes to disease progression. Notably, the effects of O-GlcNAcylation differ across disorders. This review reveals how O-GlcNAcylation bridges molecular mechanisms to neurodegeneration, as well as the prospects of targeted O-linked N-acetylglucosamine acylation therapy for neurodegenerative diseases. In Alzheimer's disease, it blocks toxic changes in key proteins like tau and amyloid-beta. In Parkinson's disease, it reduces the clumping of alpha-synuclein, yet may disrupt dopamine production. In amyotrophic lateral sclerosis, it protects nerve fiber transport systems. Additionally, O-GlcNAcylation plays an indispensable part in other neurodegenerative conditions, including Huntington's disease, aging, Machado-Joseph disease, multiple sclerosis, and giant axonal neuropathy. New therapies targeting this mechanism include glucosamine supplements and O-GlcNAcase inhibitors, which show clinical promise but face translational challenges.
PMID:
40903936
Bibliographic data and abstract were imported from PubMed on 14 Oct 2026.
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