α-Synuclein O-GlcNAcylation alters aggregation and toxicity, revealing certain residues as potential inhibitors of Parkinson’s disease
A compelling link is emerging between the posttranslational modification O-GlcNAc and protein aggregation. A prime example is α-synuclein, which forms toxic aggregates that are associated with neurodegeneration in Parkinson’s and related diseases. α-Synuclein has been shown to be O-GlcNAcylated at n...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 5; pp. 1511 - 1519 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
29.01.2019
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Series | PNAS Plus |
Subjects | |
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Abstract | A compelling link is emerging between the posttranslational modification O-GlcNAc and protein aggregation. A prime example is α-synuclein, which forms toxic aggregates that are associated with neurodegeneration in Parkinson’s and related diseases. α-Synuclein has been shown to be O-GlcNAcylated at nine different positions in in vivo proteomics experiments from mouse and human tissues. This raises the possibility that O-GlcNAc may alter the aggregation of this protein and could be both an important biological mediator of neurodegeneration and also a therapeutic target. Here, we expand upon our previous research in this area through the chemical synthesis of six site-specifically O-GlcNAcylated variants of α-synuclein. We then use a variety of biochemical experiments to show that O-GlcNAc in general inhibits the aggregation of α-synuclein but can also alter the structure of α-synuclein aggregates in site-specific ways. Additionally, an α-synuclein protein bearing three O-GlcNAc modifications can inhibit the aggregation of unmodified protein. Primary cell culture experiments also show that several of the O-GlcNAc sites inhibit the toxicity of extracellular α-synuclein fibers that are likely culprits in the spread of Parkinson’s disease. We also demonstrate that O-GlcNAcylation can inhibit the aggregation of an aggressive mutant of α-synuclein, indicating that therapies currently in development that increase this modification might be applied in animal models that rely on this mutant. Finally, we also show that the pan-selective antibody for O-GlcNAc does not generally recognize this modification on α-synuclein, potentially explaining why it remains understudied. These results support further development of O-GlcNAcylation tools and therapeutic strategies in neurodegenerative diseases. |
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AbstractList | Preventing the aggregation of toxic proteins in neurodegenerative diseases is both an important biological function and a potential therapeutic strategy. Here, we examine the consequences of O-GlcNAcylation on the aggregation and toxicity of α-synuclein, the aggregating protein in Parkinson’s disease. α-Synuclein is modified by O-GlcNAc at at least nine different positions in vivo, but the consequences of most of these modifications are unknown. Here, we use synthetic protein chemistry to prepare six different O-GlcNAcylated forms of α-synuclein and show that they have largely inhibitory, but site-specific, effects on the aggregation and cellular toxicity of this protein. These results suggest that O-GlcNAc may be a cellular strategy to prevent protein aggregation, which could potentially be exploited for treatment.
A compelling link is emerging between the posttranslational modification O-GlcNAc and protein aggregation. A prime example is α-synuclein, which forms toxic aggregates that are associated with neurodegeneration in Parkinson’s and related diseases. α-Synuclein has been shown to be O-GlcNAcylated at nine different positions in in vivo proteomics experiments from mouse and human tissues. This raises the possibility that O-GlcNAc may alter the aggregation of this protein and could be both an important biological mediator of neurodegeneration and also a therapeutic target. Here, we expand upon our previous research in this area through the chemical synthesis of six site-specifically O-GlcNAcylated variants of α-synuclein. We then use a variety of biochemical experiments to show that O-GlcNAc in general inhibits the aggregation of α-synuclein but can also alter the structure of α-synuclein aggregates in site-specific ways. Additionally, an α-synuclein protein bearing three O-GlcNAc modifications can inhibit the aggregation of unmodified protein. Primary cell culture experiments also show that several of the O-GlcNAc sites inhibit the toxicity of extracellular α-synuclein fibers that are likely culprits in the spread of Parkinson’s disease. We also demonstrate that O-GlcNAcylation can inhibit the aggregation of an aggressive mutant of α-synuclein, indicating that therapies currently in development that increase this modification might be applied in animal models that rely on this mutant. Finally, we also show that the pan-selective antibody for O-GlcNAc does not generally recognize this modification on α-synuclein, potentially explaining why it remains understudied. These results support further development of O-GlcNAcylation tools and therapeutic strategies in neurodegenerative diseases. A compelling link is emerging between the posttranslational modification O-GlcNAc and protein aggregation. A prime example is α-synuclein, which forms toxic aggregates that are associated with neurodegeneration in Parkinson's and related diseases. α-Synuclein has been shown to be O-GlcNAcylated at nine different positions in in vivo proteomics experiments from mouse and human tissues. This raises the possibility that O-GlcNAc may alter the aggregation of this protein and could be both an important biological mediator of neurodegeneration and also a therapeutic target. Here, we expand upon our previous research in this area through the chemical synthesis of six site-specifically O-GlcNAcylated variants of α-synuclein. We then use a variety of biochemical experiments to show that O-GlcNAc in general inhibits the aggregation of α-synuclein but can also alter the structure of α-synuclein aggregates in site-specific ways. Additionally, an α-synuclein protein bearing three O-GlcNAc modifications can inhibit the aggregation of unmodified protein. Primary cell culture experiments also show that several of the O-GlcNAc sites inhibit the toxicity of extracellular α-synuclein fibers that are likely culprits in the spread of Parkinson's disease. We also demonstrate that O-GlcNAcylation can inhibit the aggregation of an aggressive mutant of α-synuclein, indicating that therapies currently in development that increase this modification might be applied in animal models that rely on this mutant. Finally, we also show that the pan-selective antibody for O-GlcNAc does not generally recognize this modification on α-synuclein, potentially explaining why it remains understudied. These results support further development of O-GlcNAcylation tools and therapeutic strategies in neurodegenerative diseases. Significance Preventing the aggregation of toxic proteins in neurodegenerative diseases is both an important biological function and a potential therapeutic strategy. Here, we examine the consequences of O-GlcNAcylation on the aggregation and toxicity of α-synuclein, the aggregating protein in Parkinson’s disease. α-Synuclein is modified by O-GlcNAc at at least nine different positions in vivo, but the consequences of most of these modifications are unknown. Here, we use synthetic protein chemistry to prepare six different O-GlcNAcylated forms of α-synuclein and show that they have largely inhibitory, but site-specific, effects on the aggregation and cellular toxicity of this protein. These results suggest that O-GlcNAc may be a cellular strategy to prevent protein aggregation, which could potentially be exploited for treatment. A compelling link is emerging between the posttranslational modification O-GlcNAc and protein aggregation. A prime example is α-synuclein, which forms toxic aggregates that are associated with neurodegeneration in Parkinson’s and related diseases. α-Synuclein has been shown to be O-GlcNAcylated at nine different positions in in vivo proteomics experiments from mouse and human tissues. This raises the possibility that O-GlcNAc may alter the aggregation of this protein and could be both an important biological mediator of neurodegeneration and also a therapeutic target. Here, we expand upon our previous research in this area through the chemical synthesis of six site-specifically O-GlcNAcylated variants of α-synuclein. We then use a variety of biochemical experiments to show that O-GlcNAc in general inhibits the aggregation of α-synuclein but can also alter the structure of α-synuclein aggregates in site-specific ways. Additionally, an α-synuclein protein bearing three O-GlcNAc modifications can inhibit the aggregation of unmodified protein. Primary cell culture experiments also show that several of the O-GlcNAc sites inhibit the toxicity of extracellular α-synuclein fibers that are likely culprits in the spread of Parkinson’s disease. We also demonstrate that O-GlcNAcylation can inhibit the aggregation of an aggressive mutant of α-synuclein, indicating that therapies currently in development that increase this modification might be applied in animal models that rely on this mutant. Finally, we also show that the pan-selective antibody for O-GlcNAc does not generally recognize this modification on α-synuclein, potentially explaining why it remains understudied. These results support further development of O-GlcNAcylation tools and therapeutic strategies in neurodegenerative diseases. |
Author | Navarro, Mariana X. De Leon, Cesar A. Pratt, Matthew R. Levine, Paul M. Mahul-Mellier, Anne-Laure Lashuel, Hilal A. Balana, Aaron T. Galesic, Ana |
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BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30651314$$D View this record in MEDLINE/PubMed |
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Keywords | synuclein aggregation amyloid O-GlcNAc Parkinson’s disease |
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Notes | Edited by Carolyn R. Bertozzi, Stanford University, Stanford, CA, and approved December 14, 2018 (received for review May 23, 2018) 1P.M.L., A.G., and A.T.B. contributed equally to this work. Author contributions: P.M.L., A.G., A.T.B., A.-L.M.-M., H.A.L., and M.R.P. designed research; P.M.L., A.G., A.T.B., A.-L.M.-M., M.X.N., and C.A.D.L. performed research; P.M.L., A.G., A.T.B., and M.X.N. contributed new reagents/analytic tools; P.M.L., A.G., A.T.B., A.-L.M.-M., H.A.L., and M.R.P. analyzed data; and P.M.L., A.G., A.T.B., A.-L.M.-M., H.A.L., and M.R.P. wrote the paper. |
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Snippet | A compelling link is emerging between the posttranslational modification O-GlcNAc and protein aggregation. A prime example is α-synuclein, which forms toxic... Significance Preventing the aggregation of toxic proteins in neurodegenerative diseases is both an important biological function and a potential therapeutic... Preventing the aggregation of toxic proteins in neurodegenerative diseases is both an important biological function and a potential therapeutic strategy. Here,... |
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SubjectTerms | Acetylglucosamine - metabolism Acylation - physiology Agglomeration Aggregates alpha-Synuclein - metabolism Animal models Animals Biocompatibility Biological Sciences Cell culture Cells, Cultured Chemical synthesis Experiments Female Fibers Human tissues Mice Mice, Inbred C57BL Neurodegeneration Neurodegenerative diseases Neurological diseases O-GlcNAcylation Organic chemistry Parkinson Disease - metabolism Parkinson Disease - pathology Physical Sciences PNAS Plus Pregnancy Protein Aggregation, Pathological - pathology Protein interaction Protein Processing, Post-Translational - physiology Proteins Proteomics Synuclein Therapeutic applications Toxicity |
Title | α-Synuclein O-GlcNAcylation alters aggregation and toxicity, revealing certain residues as potential inhibitors of Parkinson’s disease |
URI | https://www.jstor.org/stable/26580279 https://www.ncbi.nlm.nih.gov/pubmed/30651314 https://www.proquest.com/docview/2176699969/abstract/ https://pubmed.ncbi.nlm.nih.gov/PMC6358670 |
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