O-GlcNAc modification blocks the aggregation and toxicity of the protein α-synuclein associated with Parkinson's disease.
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, α-synuclein, is a toxic aggregating protein associated with synucleinopathies, including Parkinson's disease. However, the effect of O-GlcNAcylation on α-synuclein is not clear. Here, we use synthetic protein chemistry to generate both unmodified α-synuclein and α-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 α-synuclein aggregation, while not affecting the membrane binding or bending properties of α-synuclein. O-GlcNAcylation is also shown to affect the phosphorylation of α-synuclein in vitro and block the toxicity of α-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.
Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA.
Nicholas P
NP
Marotta
Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA.
Yu Hsuan
YH
Lin
Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA.
Yuka E
YE
Lewis
Department of Biochemistry and Molecular Biology and the Zilka Neurogenetic Institute, University of Southern California, Los Angeles, California 90089, USA.
Mark R
MR
Ambroso
Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA.
Balyn W
BW
Zaro
Department of Molecular and Computational Biology, University of Southern California, Los Angeles, California 90089, USA.
Maxwell T
MT
Roth
Department of Molecular and Computational Biology, University of Southern California, Los Angeles, California 90089, USA.
Don B
DB
Arnold
Department of Biochemistry and Molecular Biology and the Zilka Neurogenetic Institute, University of Southern California, Los Angeles, California 90089, USA.
Ralf
R
Langen
Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA.|Department of Molecular and Computational Biology, University of Southern California, Los Angeles, California 90089, USA.
Matthew R
MR
Pratt
D000117:Acetylglucosamine / Q000737:chemistry*; D000215:Acylation; D006801:Humans; D010300:Parkinson Disease / Q000378:metabolism*; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
D051844:alpha-Synuclein; D000117:Acetylglucosamine