Revealing Well-Defined Soluble States during Amyloid Fibril Formation by Multilinear Analysis of NMR Diffusion Data

Kristine Steen Jensen, Sara Linse, Mathias Nilsson, Mikael Akke, Anders Malmendal

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Amyloid fibril formation is a hallmark of neurodegenerative disease caused by protein aggregation. Oligomeric protein states that arise during the process of fibril formation often coexist with mature fibrils and are known to cause cell death in disease model systems. Progress in this field depends critically on development of analytical methods that can provide information about the mechanisms and species involved in oligomerization and fibril formation. Here, we demonstrate how the powerful combination of diffusion NMR and multilinear data analysis can efficiently disentangle the number of involved species, their kinetic rates of formation or disappearance, spectral contributions, and diffusion coefficients, even without prior knowledge of the time evolution of the process or chemical shift assignments of the various species. Using this method we identify oligomeric species that form transiently during aggregation of human superoxide dismutase 1 (SOD1), which is known to form misfolded aggregates in patients with amyotrophic lateral sclerosis. Specifically, over a time course of 42 days, during which SOD1 fibrils form, we detect the disappearance of the native monomeric species, formation of a partially unfolded intermediate in the dimer to tetramer size range, subsequent formation of a distinct similarly sized species that dominates the final spectrum detected by solution NMR, and concomitant appearance of small peptide fragments.
OriginalsprogEngelsk
TidsskriftJournal of the American Chemical Society
Vol/bind141
Udgave nummer47
Sider (fra-til)18649-18652
Antal sider4
ISSN0002-7863
DOI
StatusUdgivet - 13 nov. 2019

Citer dette

Jensen, Kristine Steen ; Linse, Sara ; Nilsson, Mathias ; Akke, Mikael ; Malmendal, Anders. / Revealing Well-Defined Soluble States during Amyloid Fibril Formation by Multilinear Analysis of NMR Diffusion Data. I: Journal of the American Chemical Society. 2019 ; Bind 141, Nr. 47. s. 18649-18652.
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abstract = "Amyloid fibril formation is a hallmark of neurodegenerative disease caused by protein aggregation. Oligomeric protein states that arise during the process of fibril formation often coexist with mature fibrils and are known to cause cell death in disease model systems. Progress in this field depends critically on development of analytical methods that can provide information about the mechanisms and species involved in oligomerization and fibril formation. Here, we demonstrate how the powerful combination of diffusion NMR and multilinear data analysis can efficiently disentangle the number of involved species, their kinetic rates of formation or disappearance, spectral contributions, and diffusion coefficients, even without prior knowledge of the time evolution of the process or chemical shift assignments of the various species. Using this method we identify oligomeric species that form transiently during aggregation of human superoxide dismutase 1 (SOD1), which is known to form misfolded aggregates in patients with amyotrophic lateral sclerosis. Specifically, over a time course of 42 days, during which SOD1 fibrils form, we detect the disappearance of the native monomeric species, formation of a partially unfolded intermediate in the dimer to tetramer size range, subsequent formation of a distinct similarly sized species that dominates the final spectrum detected by solution NMR, and concomitant appearance of small peptide fragments.",
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Revealing Well-Defined Soluble States during Amyloid Fibril Formation by Multilinear Analysis of NMR Diffusion Data. / Jensen, Kristine Steen; Linse, Sara; Nilsson, Mathias; Akke, Mikael; Malmendal, Anders.

I: Journal of the American Chemical Society, Bind 141, Nr. 47, 13.11.2019, s. 18649-18652.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Revealing Well-Defined Soluble States during Amyloid Fibril Formation by Multilinear Analysis of NMR Diffusion Data

AU - Jensen, Kristine Steen

AU - Linse, Sara

AU - Nilsson, Mathias

AU - Akke, Mikael

AU - Malmendal, Anders

PY - 2019/11/13

Y1 - 2019/11/13

N2 - Amyloid fibril formation is a hallmark of neurodegenerative disease caused by protein aggregation. Oligomeric protein states that arise during the process of fibril formation often coexist with mature fibrils and are known to cause cell death in disease model systems. Progress in this field depends critically on development of analytical methods that can provide information about the mechanisms and species involved in oligomerization and fibril formation. Here, we demonstrate how the powerful combination of diffusion NMR and multilinear data analysis can efficiently disentangle the number of involved species, their kinetic rates of formation or disappearance, spectral contributions, and diffusion coefficients, even without prior knowledge of the time evolution of the process or chemical shift assignments of the various species. Using this method we identify oligomeric species that form transiently during aggregation of human superoxide dismutase 1 (SOD1), which is known to form misfolded aggregates in patients with amyotrophic lateral sclerosis. Specifically, over a time course of 42 days, during which SOD1 fibrils form, we detect the disappearance of the native monomeric species, formation of a partially unfolded intermediate in the dimer to tetramer size range, subsequent formation of a distinct similarly sized species that dominates the final spectrum detected by solution NMR, and concomitant appearance of small peptide fragments.

AB - Amyloid fibril formation is a hallmark of neurodegenerative disease caused by protein aggregation. Oligomeric protein states that arise during the process of fibril formation often coexist with mature fibrils and are known to cause cell death in disease model systems. Progress in this field depends critically on development of analytical methods that can provide information about the mechanisms and species involved in oligomerization and fibril formation. Here, we demonstrate how the powerful combination of diffusion NMR and multilinear data analysis can efficiently disentangle the number of involved species, their kinetic rates of formation or disappearance, spectral contributions, and diffusion coefficients, even without prior knowledge of the time evolution of the process or chemical shift assignments of the various species. Using this method we identify oligomeric species that form transiently during aggregation of human superoxide dismutase 1 (SOD1), which is known to form misfolded aggregates in patients with amyotrophic lateral sclerosis. Specifically, over a time course of 42 days, during which SOD1 fibrils form, we detect the disappearance of the native monomeric species, formation of a partially unfolded intermediate in the dimer to tetramer size range, subsequent formation of a distinct similarly sized species that dominates the final spectrum detected by solution NMR, and concomitant appearance of small peptide fragments.

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DO - 10.1021/jacs.9b07952

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