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

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.

In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice

“…Because of the low bioavailibility of curcumin, formulation has been a focus for enabling treatment. The posttranslational modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc) inhibits protein aggregation in multiple neurodegenerative diseases [72]. An oral inhibitor of O-GlcNAcase reduces tauopathy in rTg4510 mice [73] and has entered clinical development for progressive supranuclear palsy [74,75].…”

The Glucose Metabolic Pathway as A Potential Target for Therapeutics: Crucial Role of Glycosylation in Alzheimer’s Disease

“…The hexosamine biosynthetic pathway (HBP) is a branch of the glycolysis that is responsible for the production of UDP-GlcNAc, a key substrate for protein glycosylation. O-GlcNAc is closely regulated by cellular glucose concentrations and 2 to 3% of total glucose is transformed into UDP-GlcNAc [ 36 ]. Therefore, O-GlcNAcylation is considered a nutrient sensor and its dependence is not only confined to glucose metabolism but also influenced by amino acid (glutamine), fatty acids (acetyl-CoA) and nucleotide (uridine triphosphate) [ 37 , 38 ].…”

Considerations for future tau-targeted therapeutics: can they deliver?

“…The first studies using the O-GlcNAcylase inhibitors ASN120290 are underway for PSP. Importantly, target engagement will be aided in these studies by the use of specific PET tracers against O-GlcNAcylase enzymes [10].…”