O-GlcNAc modification blocks the aggregation and toxicity of the protein ?-synuclein associated with Parkinson's disease.

ABSTRACT: Several aggregation-prone proteins associated with neurodegenerative diseases can be modified by O-linked N-acetyl-glucosamine (O-GlcNAc) in vivo. One of these proteins, ?-synuclein, is a toxic aggregating protein associated with synucleinopathies, including Parkinson's disease. However, the effect of O-GlcNAcylation on ?-synuclein is not clear. Here, we use synthetic protein chemistry to generate both unmodified ?-synuclein and ?-synuclein bearing a site-specific O-GlcNAc modification at the physiologically relevant threonine residue 72. We show that this single modification has a notable and substoichiometric inhibitory effect on ?-synuclein aggregation, while not affecting the membrane binding or bending properties of ?-synuclein. O-GlcNAcylation is also shown to affect the phosphorylation of ?-synuclein in vitro and block the toxicity of ?-synuclein that was exogenously added to cells in culture. These results suggest that increasing O-GlcNAcylation may slow the progression of synucleinopathies and further support a general function for O-GlcNAc in preventing protein aggregation.

SUBMITTER: Marotta NP 

PROVIDER: S-EPMC4618406 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature