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Distinct neurotoxic TDP-43 fibril polymorphs are generated by heterotypic interactions with α-Synuclein.

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Title: Distinct neurotoxic TDP-43 fibril polymorphs are generated by heterotypic interactions with α-Synuclein.
Authors: Dhakal, Shailendra1,2, Robang, Alicia S.3, Bhatt, Nemil4, Puangmalai, Nicha4, Fung, Leiana4, Kayed, Rakez4, Paravastu, Anant K.3 anant.paravastu@chbe.gatech.edu, Rangachari, Vijayaraghavan1,2 vijay.rangachari@usm.edu
Source: Journal of Biological Chemistry. Nov2022, Vol. 298 Issue 11, p1-15. 15p.
Subjects: Alpha-synuclein, Lewy body dementia, DNA-binding proteins, TDP-43 proteinopathies, Gold nanoparticles, Amyloid beta-protein, Amyloid
Abstract: Amyloid aggregates of specific proteins constitute important pathological hallmarks in many neurodegenerative diseases, defining neuronal degeneration and disease onset. Recently, increasing numbers of patients show comorbidities and overlaps between multiple neurodegenerative diseases, presenting distinct phenotypes. Such overlaps are often accompanied by colocalizations of more than one amyloid protein, prompting the question of whether direct interactions between different amyloid proteins could generate heterotypic amyloids. To answer this question, we investigated the effect of α-synuclein (αS) on the DNA-binding protein TDP-43 aggregation inspired by their coexistence in pathologies such as Lewy body dementia and limbic predominant age-related TDP-43 encephalopathy. We previously showed αS and prion-like C-terminal domain (PrLD) of TDP-43 synergistically interact to generate toxic heterotypic aggregates. Here, we extend these studies to investigate whether αS induces structurally and functionally distinct polymorphs of PrLD aggregates. Using αS-PrLD heterotypic aggregates generated in two different stoichiometric proportions, we show αS can affect PrLD fibril forms. PrLD fibrils show distinctive residue level signatures determined by solid state NMR, dye-binding capability, proteinase K (PK) stability, and thermal stability toward SDS denaturation. Furthremore, by gold nanoparticle labeling and transmission electron microscopy, we show the presence of both αS and PrLD proteins within the same fibrils, confirming the existence of heterotypic amyloid fibrils. We also observe αS and PrLD colocalize in the cytosol of neuroblastoma cells and show that the heterotypic PrLD fibrils selectively induce synaptic dysfunction in primary neurons. These findings establish the existence of heterotypic amyloid and provide a molecular basis for the observed overlap between synucleinopathies and TDP-43 proteinopathies. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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DbLabel: Engineering Source
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  Data: Distinct neurotoxic TDP-43 fibril polymorphs are generated by heterotypic interactions with α-Synuclein.
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  Data: <searchLink fieldCode="AR" term="%22Dhakal%2C+Shailendra%22">Dhakal, Shailendra</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Robang%2C+Alicia+S%2E%22">Robang, Alicia S.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Bhatt%2C+Nemil%22">Bhatt, Nemil</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Puangmalai%2C+Nicha%22">Puangmalai, Nicha</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Fung%2C+Leiana%22">Fung, Leiana</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Kayed%2C+Rakez%22">Kayed, Rakez</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Paravastu%2C+Anant+K%2E%22">Paravastu, Anant K.</searchLink><relatesTo>3</relatesTo><i> anant.paravastu@chbe.gatech.edu</i><br /><searchLink fieldCode="AR" term="%22Rangachari%2C+Vijayaraghavan%22">Rangachari, Vijayaraghavan</searchLink><relatesTo>1,2</relatesTo><i> vijay.rangachari@usm.edu</i>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. Nov2022, Vol. 298 Issue 11, p1-15. 15p.
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  Data: <searchLink fieldCode="DE" term="%22Alpha-synuclein%22">Alpha-synuclein</searchLink><br /><searchLink fieldCode="DE" term="%22Lewy+body+dementia%22">Lewy body dementia</searchLink><br /><searchLink fieldCode="DE" term="%22DNA-binding+proteins%22">DNA-binding proteins</searchLink><br /><searchLink fieldCode="DE" term="%22TDP-43+proteinopathies%22">TDP-43 proteinopathies</searchLink><br /><searchLink fieldCode="DE" term="%22Gold+nanoparticles%22">Gold nanoparticles</searchLink><br /><searchLink fieldCode="DE" term="%22Amyloid+beta-protein%22">Amyloid beta-protein</searchLink><br /><searchLink fieldCode="DE" term="%22Amyloid%22">Amyloid</searchLink>
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  Data: Amyloid aggregates of specific proteins constitute important pathological hallmarks in many neurodegenerative diseases, defining neuronal degeneration and disease onset. Recently, increasing numbers of patients show comorbidities and overlaps between multiple neurodegenerative diseases, presenting distinct phenotypes. Such overlaps are often accompanied by colocalizations of more than one amyloid protein, prompting the question of whether direct interactions between different amyloid proteins could generate heterotypic amyloids. To answer this question, we investigated the effect of α-synuclein (αS) on the DNA-binding protein TDP-43 aggregation inspired by their coexistence in pathologies such as Lewy body dementia and limbic predominant age-related TDP-43 encephalopathy. We previously showed αS and prion-like C-terminal domain (PrLD) of TDP-43 synergistically interact to generate toxic heterotypic aggregates. Here, we extend these studies to investigate whether αS induces structurally and functionally distinct polymorphs of PrLD aggregates. Using αS-PrLD heterotypic aggregates generated in two different stoichiometric proportions, we show αS can affect PrLD fibril forms. PrLD fibrils show distinctive residue level signatures determined by solid state NMR, dye-binding capability, proteinase K (PK) stability, and thermal stability toward SDS denaturation. Furthremore, by gold nanoparticle labeling and transmission electron microscopy, we show the presence of both αS and PrLD proteins within the same fibrils, confirming the existence of heterotypic amyloid fibrils. We also observe αS and PrLD colocalize in the cytosol of neuroblastoma cells and show that the heterotypic PrLD fibrils selectively induce synaptic dysfunction in primary neurons. These findings establish the existence of heterotypic amyloid and provide a molecular basis for the observed overlap between synucleinopathies and TDP-43 proteinopathies. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
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      – Type: doi
        Value: 10.1016/j.jbc.2022.102498
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      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 15
        StartPage: 1
    Subjects:
      – SubjectFull: Alpha-synuclein
        Type: general
      – SubjectFull: Lewy body dementia
        Type: general
      – SubjectFull: DNA-binding proteins
        Type: general
      – SubjectFull: TDP-43 proteinopathies
        Type: general
      – SubjectFull: Gold nanoparticles
        Type: general
      – SubjectFull: Amyloid beta-protein
        Type: general
      – SubjectFull: Amyloid
        Type: general
    Titles:
      – TitleFull: Distinct neurotoxic TDP-43 fibril polymorphs are generated by heterotypic interactions with α-Synuclein.
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            NameFull: Dhakal, Shailendra
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            NameFull: Robang, Alicia S.
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            NameFull: Bhatt, Nemil
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            NameFull: Puangmalai, Nicha
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            NameFull: Fung, Leiana
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            NameFull: Rangachari, Vijayaraghavan
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            – D: 01
              M: 11
              Text: Nov2022
              Type: published
              Y: 2022
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