Computationally Designed Molecules Modulate ALS-Related Amyloidogenic TDP-43307-319 Aggregation
Abnormal cytosolic aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) is observed in multiple diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and Alzheimer's disease. Previous studies have shown that TDP-43307-319 located at the C-terminal of TDP-43 can form higher-order oligomers and fibrils. Of particular interest are the hexamers that adopt a cylindrin structure that has been strongly correlated to neurotoxicity. In this study, we use the joint pharmacophore space (JPS) model to identify and generate potential TDP-43 inhibitors. Five JPS-designed molecules are evaluated using both experimental and computational methods: ion mobility mass spectrometry, thioflavin T fluorescence assay, circular dichroism spectroscopy, atomic force microscopy, and molecular dynamics simulations. We found that all five molecules can prevent the amyloid fibril formation of TDP-43307-319, but their efficacy varies significantly. Furthermore, among the five molecules, [AC0101] is the most efficient in preventing the formation of higher-order oligomers and dissociating preformed higher-order oligomers. Molecular dynamics simulations show that [AC0101] both is the most flexible and forms the most hydrogen bonds with the TDP-43307-319 monomer. The JPS-designed molecules can insert themselves between the β-strands in the hexameric cylindrin structure of TDP-43307-319 and can open its structure. Possible mechanisms for JPS-designed molecules to inhibit and dissociate TDP-43307-319 oligomers on an atomistic scale are proposed.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
ACS chemical neuroscience - 14(2023), 24 vom: 20. Dez., Seite 4395-4408 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liu, Xikun [VerfasserIn] |
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| Links: |
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| Themen: |
ALS |
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| Anmerkungen: |
Date Completed 21.12.2023 Date Revised 21.12.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acschemneuro.3c00582 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Abnormal cytosolic aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) is observed in multiple diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and Alzheimer's disease. Previous studies have shown that TDP-43307-319 located at the C-terminal of TDP-43 can form higher-order oligomers and fibrils. Of particular interest are the hexamers that adopt a cylindrin structure that has been strongly correlated to neurotoxicity. In this study, we use the joint pharmacophore space (JPS) model to identify and generate potential TDP-43 inhibitors. Five JPS-designed molecules are evaluated using both experimental and computational methods: ion mobility mass spectrometry, thioflavin T fluorescence assay, circular dichroism spectroscopy, atomic force microscopy, and molecular dynamics simulations. We found that all five molecules can prevent the amyloid fibril formation of TDP-43307-319, but their efficacy varies significantly. Furthermore, among the five molecules, [AC0101] is the most efficient in preventing the formation of higher-order oligomers and dissociating preformed higher-order oligomers. Molecular dynamics simulations show that [AC0101] both is the most flexible and forms the most hydrogen bonds with the TDP-43307-319 monomer. The JPS-designed molecules can insert themselves between the β-strands in the hexameric cylindrin structure of TDP-43307-319 and can open its structure. Possible mechanisms for JPS-designed molecules to inhibit and dissociate TDP-43307-319 oligomers on an atomistic scale are proposed | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Duan, Shuya |e verfasserin |4 aut | |
| 700 | 1 | |a Jin, Yingying |e verfasserin |4 aut | |
| 700 | 1 | |a Walker, Ethan |e verfasserin |4 aut | |
| 700 | 1 | |a Tsao, Michelle |e verfasserin |4 aut | |
| 700 | 1 | |a Jang, Joshua H |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Ziying |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Ambuj K |e verfasserin |4 aut | |
| 700 | 1 | |a Cantrell, Kristi Lazar |e verfasserin |4 aut | |
| 700 | 1 | |a Ingolfsson, Helgi I |e verfasserin |4 aut | |
| 700 | 1 | |a Buratto, Steven K |e verfasserin |4 aut | |
| 700 | 1 | |a Bowers, Michael T |e verfasserin |4 aut | |
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