O-GlcNAc Modification Protects against Protein Misfolding and Aggregation in Neurodegenerative Disease

Philip Ryan, Mingming Xu, Andrew K. Davey, Jonathan J. Danon, George D. Mellick, Michael Kassiou*, Santosh Rudrawar

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

55 Citations (Scopus)

Abstract

Post-translational modifications (PTMs) of proteins are becoming the focus of intense research due to their implications in a broad spectrum of neurodegenerative diseases. Various PTMs have been identified to alter the toxic profiles of proteins which play critical roles in disease etiology. In Alzheimer's disease (AD), dysregulated phosphorylation is reported to promote pathogenic processing of the microtubule-associated tau protein. Among the PTMs, the enzymatic addition of N-acetyl-d-glucosamine (GlcNAc) residues to Ser/Thr residues is reported to deliver protective effects against the pathogenic processing of both amyloid precursor protein (APP) and tau. Modification of tau with as few as one single O-GlcNAc residue inhibits its toxic self-assembly. This modification also has the same effect on the assembly of the Parkinson's disease (PD) associated α-synuclein (ASyn) protein. In fact, O-GlcNAcylation (O-linked GlcNAc modification) affects the processing of numerous proteins implicated in AD, PD, amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) in a similar manner. As such, manipulation of a protein's O-GlcNAcylation status has been proposed to offer therapeutic routes toward addressing multiple neurodegenerative pathologies. Here we review the various effects that O-GlcNAc modification, and its modulated expression, have on pathogenically significant proteins involved in neurodegenerative disease.

Original languageEnglish
Pages (from-to)2209-2221
Number of pages13
JournalACS Chemical Neuroscience
Volume10
Issue number5
DOIs
Publication statusPublished - 15 May 2019
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Amyloid
  • GlcNAc
  • OGT
  • Parkinson's disease
  • glycopeptides
  • glycosylation.
  • neurodegenerative disease
  • peptides
  • synuclein
  • tau

Fingerprint

Dive into the research topics of 'O-GlcNAc Modification Protects against Protein Misfolding and Aggregation in Neurodegenerative Disease'. Together they form a unique fingerprint.

Cite this