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Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation

Academic Article
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Overview

authors

  • Yuzwa, S. A.
  • Shan, X.
  • Macauley, Matthew
  • Clark, T.
  • Skorobogatko, Y.
  • Vosseller, K.
  • Vocadlo, D. J.

publication date

  • April 2012

journal

  • Nature Chemical Biology  Journal

abstract

  • Oligomerization of tau is a key process contributing to the progressive death of neurons in Alzheimer's disease. Tau is modified by O-linked N-acetylglucosamine (O-GlcNAc), and O-GlcNAc can influence tau phosphorylation in certain cases. We therefore speculated that increasing tau O-GlcNAc could be a strategy to hinder pathological tau-induced neurodegeneration. Here we found that treatment of hemizygous JNPL3 tau transgenic mice with an O-GlcNAcase inhibitor increased tau O-GlcNAc, hindered formation of tau aggregates and decreased neuronal cell loss. Notably, increases in tau O-GlcNAc did not alter tau phosphorylation in vivo. Using in vitro biochemical aggregation studies, we found that O-GlcNAc modification, on its own, hinders tau oligomerization. O-GlcNAc also inhibits thermally induced aggregation of an unrelated protein, TAK-1 binding protein, suggesting that a basic biochemical function of O-GlcNAc may be to prevent protein aggregation. These results also suggest O-GlcNAcase as a potential therapeutic target that could hinder progression of Alzheimer's disease.

subject areas

  • Acetylglucosamine
  • Adaptor Proteins, Signal Transducing
  • Alzheimer Disease
  • Animals
  • Carbohydrate Conformation
  • Disease Models, Animal
  • Enzyme Inhibitors
  • Female
  • Humans
  • Mice
  • Mice, Transgenic
  • N-Acetylglucosaminyltransferases
  • Neurodegenerative Diseases
  • Neurons
  • Phosphorylation
  • Pyrans
  • Thiazoles
  • tau Proteins
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Identity

International Standard Serial Number (ISSN)

  • 1552-4450

Digital Object Identifier (DOI)

  • 10.1038/nchembio.797

PubMed ID

  • 22366723
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Additional Document Info

start page

  • 393

end page

  • 399

volume

  • 8

issue

  • 4

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