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O-GlcNAc modification forces the formation of an α-Synuclein amyloid-strain with notably diminished seeding activity and pathology

The process of amyloid fibril formation remains one of the primary targets for developing diagnostics and treatments for several neurodegenerative diseases (NDDs). Amyloid-forming proteins such α-Synuclein and Tau, which are implicated in the pathogenesis of Alzheimer’s and Parkinson’s disease, can...

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Autores principales: Balana, Aaron T., Mahul-Mellier, Anne-Laure, Nguyen, Binh A, Horvath, Mian, Javed, Afraah, Hard, Eldon R., Jasiqi, Yllza, Singh, Preeti, Afrin, Shumaila, Pedretti, Rose, Singh, Virender, Lee, Virginia M.-Y., Luk, Kelvin C., Saelices, Lorena, Lashuel, Hilal A., Pratt, Matthew R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10028859/
https://www.ncbi.nlm.nih.gov/pubmed/36945566
http://dx.doi.org/10.1101/2023.03.07.531573
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author Balana, Aaron T.
Mahul-Mellier, Anne-Laure
Nguyen, Binh A
Horvath, Mian
Javed, Afraah
Hard, Eldon R.
Jasiqi, Yllza
Singh, Preeti
Afrin, Shumaila
Pedretti, Rose
Singh, Virender
Lee, Virginia M.-Y.
Luk, Kelvin C.
Saelices, Lorena
Lashuel, Hilal A.
Pratt, Matthew R.
author_facet Balana, Aaron T.
Mahul-Mellier, Anne-Laure
Nguyen, Binh A
Horvath, Mian
Javed, Afraah
Hard, Eldon R.
Jasiqi, Yllza
Singh, Preeti
Afrin, Shumaila
Pedretti, Rose
Singh, Virender
Lee, Virginia M.-Y.
Luk, Kelvin C.
Saelices, Lorena
Lashuel, Hilal A.
Pratt, Matthew R.
author_sort Balana, Aaron T.
collection PubMed
description The process of amyloid fibril formation remains one of the primary targets for developing diagnostics and treatments for several neurodegenerative diseases (NDDs). Amyloid-forming proteins such α-Synuclein and Tau, which are implicated in the pathogenesis of Alzheimer’s and Parkinson’s disease, can form different types of fibril structure, or strains, that exhibit distinct structures, toxic properties, seeding activities, and pathology spreading patterns in the brain. Therefore, understanding the molecular and structural determinants contributing to the formation of different amyloid strains or their distinct features could open new avenues for developing disease-specific diagnostics and therapies. In this work, we report that O-GlcNAc modification of α-Synuclein monomers results in the formation of amyloid fibril with distinct core structure, as revealed by Cryo-EM, and diminished seeding activity in seeding-based neuronal and rodent models of Parkinson’s disease. Although the mechanisms underpinning the seeding neutralization activity of the O-GlcNAc modified fibrils remain unclear, our in vitro mechanistic studies indicate that heat shock proteins interactions with O-GlcNAc fibril inhibit their seeding activity, suggesting that the O-GlcNAc modification may alter the interactome of the α-Synuclein fibrils in ways that lead to reduce seeding activity in vivo. Our results show that post-translational modifications, such as O-GlcNAc modification, of α-Synuclein are key determinants of α-Synuclein amyloid strains and pathogenicity. These findings have significant implications for how we investigate and target amyloids in the brain and could possibly explain the lack of correlation between amyloid burden and neurodegeneration or cognitive decline in some subtypes of NDDs.
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spelling pubmed-100288592023-03-22 O-GlcNAc modification forces the formation of an α-Synuclein amyloid-strain with notably diminished seeding activity and pathology Balana, Aaron T. Mahul-Mellier, Anne-Laure Nguyen, Binh A Horvath, Mian Javed, Afraah Hard, Eldon R. Jasiqi, Yllza Singh, Preeti Afrin, Shumaila Pedretti, Rose Singh, Virender Lee, Virginia M.-Y. Luk, Kelvin C. Saelices, Lorena Lashuel, Hilal A. Pratt, Matthew R. bioRxiv Article The process of amyloid fibril formation remains one of the primary targets for developing diagnostics and treatments for several neurodegenerative diseases (NDDs). Amyloid-forming proteins such α-Synuclein and Tau, which are implicated in the pathogenesis of Alzheimer’s and Parkinson’s disease, can form different types of fibril structure, or strains, that exhibit distinct structures, toxic properties, seeding activities, and pathology spreading patterns in the brain. Therefore, understanding the molecular and structural determinants contributing to the formation of different amyloid strains or their distinct features could open new avenues for developing disease-specific diagnostics and therapies. In this work, we report that O-GlcNAc modification of α-Synuclein monomers results in the formation of amyloid fibril with distinct core structure, as revealed by Cryo-EM, and diminished seeding activity in seeding-based neuronal and rodent models of Parkinson’s disease. Although the mechanisms underpinning the seeding neutralization activity of the O-GlcNAc modified fibrils remain unclear, our in vitro mechanistic studies indicate that heat shock proteins interactions with O-GlcNAc fibril inhibit their seeding activity, suggesting that the O-GlcNAc modification may alter the interactome of the α-Synuclein fibrils in ways that lead to reduce seeding activity in vivo. Our results show that post-translational modifications, such as O-GlcNAc modification, of α-Synuclein are key determinants of α-Synuclein amyloid strains and pathogenicity. These findings have significant implications for how we investigate and target amyloids in the brain and could possibly explain the lack of correlation between amyloid burden and neurodegeneration or cognitive decline in some subtypes of NDDs. Cold Spring Harbor Laboratory 2023-03-07 /pmc/articles/PMC10028859/ /pubmed/36945566 http://dx.doi.org/10.1101/2023.03.07.531573 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Balana, Aaron T.
Mahul-Mellier, Anne-Laure
Nguyen, Binh A
Horvath, Mian
Javed, Afraah
Hard, Eldon R.
Jasiqi, Yllza
Singh, Preeti
Afrin, Shumaila
Pedretti, Rose
Singh, Virender
Lee, Virginia M.-Y.
Luk, Kelvin C.
Saelices, Lorena
Lashuel, Hilal A.
Pratt, Matthew R.
O-GlcNAc modification forces the formation of an α-Synuclein amyloid-strain with notably diminished seeding activity and pathology
title O-GlcNAc modification forces the formation of an α-Synuclein amyloid-strain with notably diminished seeding activity and pathology
title_full O-GlcNAc modification forces the formation of an α-Synuclein amyloid-strain with notably diminished seeding activity and pathology
title_fullStr O-GlcNAc modification forces the formation of an α-Synuclein amyloid-strain with notably diminished seeding activity and pathology
title_full_unstemmed O-GlcNAc modification forces the formation of an α-Synuclein amyloid-strain with notably diminished seeding activity and pathology
title_short O-GlcNAc modification forces the formation of an α-Synuclein amyloid-strain with notably diminished seeding activity and pathology
title_sort o-glcnac modification forces the formation of an α-synuclein amyloid-strain with notably diminished seeding activity and pathology
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10028859/
https://www.ncbi.nlm.nih.gov/pubmed/36945566
http://dx.doi.org/10.1101/2023.03.07.531573
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