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Distinct responses of neurons and astrocytes to TDP-43 proteinopathy in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease caused by motor neuron loss, resulting in muscle wasting, paralysis and eventual death. A key pathological feature of ALS is cytoplasmically mislocalized and aggregated TDP-43 protein in >95% of cases, which is...

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Autores principales: Smethurst, Phillip, Risse, Emmanuel, Tyzack, Giulia E, Mitchell, Jamie S, Taha, Doaa M, Chen, Yun-Ru, Newcombe, Jia, Collinge, John, Sidle, Katie, Patani, Rickie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7009461/
https://www.ncbi.nlm.nih.gov/pubmed/32040555
http://dx.doi.org/10.1093/brain/awz419
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author Smethurst, Phillip
Risse, Emmanuel
Tyzack, Giulia E
Mitchell, Jamie S
Taha, Doaa M
Chen, Yun-Ru
Newcombe, Jia
Collinge, John
Sidle, Katie
Patani, Rickie
author_facet Smethurst, Phillip
Risse, Emmanuel
Tyzack, Giulia E
Mitchell, Jamie S
Taha, Doaa M
Chen, Yun-Ru
Newcombe, Jia
Collinge, John
Sidle, Katie
Patani, Rickie
author_sort Smethurst, Phillip
collection PubMed
description Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease caused by motor neuron loss, resulting in muscle wasting, paralysis and eventual death. A key pathological feature of ALS is cytoplasmically mislocalized and aggregated TDP-43 protein in >95% of cases, which is considered to have prion-like properties. Historical studies have predominantly focused on genetic forms of ALS, which represent ∼10% of cases, leaving the remaining 90% of sporadic ALS relatively understudied. Additionally, the role of astrocytes in ALS and their relationship with TDP-43 pathology is also not currently well understood. We have therefore used highly enriched human induced pluripotent stem cell (iPSC)-derived motor neurons and astrocytes to model early cell type-specific features of sporadic ALS. We first demonstrate seeded aggregation of TDP-43 by exposing human iPSC-derived motor neurons to serially passaged sporadic ALS post-mortem tissue (spALS) extracts. Next, we show that human iPSC-derived motor neurons are more vulnerable to TDP-43 aggregation and toxicity compared with their astrocyte counterparts. We demonstrate that these TDP-43 aggregates can more readily propagate from motor neurons into astrocytes in co-culture paradigms. We next found that astrocytes are neuroprotective to seeded aggregation within motor neurons by reducing (mislocalized) cytoplasmic TDP-43, TDP-43 aggregation and cell toxicity. Furthermore, we detected TDP-43 oligomers in these spALS spinal cord extracts, and as such demonstrated that highly purified recombinant TDP-43 oligomers can reproduce this observed cell-type specific toxicity, providing further support to a protein oligomer-mediated toxicity hypothesis in ALS. In summary, we have developed a human, clinically relevant, and cell-type specific modelling platform that recapitulates key aspects of sporadic ALS and uncovers both an initial neuroprotective role for astrocytes and the cell type-specific toxic effect of TDP-43 oligomers.
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spelling pubmed-70094612020-02-13 Distinct responses of neurons and astrocytes to TDP-43 proteinopathy in amyotrophic lateral sclerosis Smethurst, Phillip Risse, Emmanuel Tyzack, Giulia E Mitchell, Jamie S Taha, Doaa M Chen, Yun-Ru Newcombe, Jia Collinge, John Sidle, Katie Patani, Rickie Brain Reports Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease caused by motor neuron loss, resulting in muscle wasting, paralysis and eventual death. A key pathological feature of ALS is cytoplasmically mislocalized and aggregated TDP-43 protein in >95% of cases, which is considered to have prion-like properties. Historical studies have predominantly focused on genetic forms of ALS, which represent ∼10% of cases, leaving the remaining 90% of sporadic ALS relatively understudied. Additionally, the role of astrocytes in ALS and their relationship with TDP-43 pathology is also not currently well understood. We have therefore used highly enriched human induced pluripotent stem cell (iPSC)-derived motor neurons and astrocytes to model early cell type-specific features of sporadic ALS. We first demonstrate seeded aggregation of TDP-43 by exposing human iPSC-derived motor neurons to serially passaged sporadic ALS post-mortem tissue (spALS) extracts. Next, we show that human iPSC-derived motor neurons are more vulnerable to TDP-43 aggregation and toxicity compared with their astrocyte counterparts. We demonstrate that these TDP-43 aggregates can more readily propagate from motor neurons into astrocytes in co-culture paradigms. We next found that astrocytes are neuroprotective to seeded aggregation within motor neurons by reducing (mislocalized) cytoplasmic TDP-43, TDP-43 aggregation and cell toxicity. Furthermore, we detected TDP-43 oligomers in these spALS spinal cord extracts, and as such demonstrated that highly purified recombinant TDP-43 oligomers can reproduce this observed cell-type specific toxicity, providing further support to a protein oligomer-mediated toxicity hypothesis in ALS. In summary, we have developed a human, clinically relevant, and cell-type specific modelling platform that recapitulates key aspects of sporadic ALS and uncovers both an initial neuroprotective role for astrocytes and the cell type-specific toxic effect of TDP-43 oligomers. Oxford University Press 2020-02 2020-02-10 /pmc/articles/PMC7009461/ /pubmed/32040555 http://dx.doi.org/10.1093/brain/awz419 Text en © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Reports
Smethurst, Phillip
Risse, Emmanuel
Tyzack, Giulia E
Mitchell, Jamie S
Taha, Doaa M
Chen, Yun-Ru
Newcombe, Jia
Collinge, John
Sidle, Katie
Patani, Rickie
Distinct responses of neurons and astrocytes to TDP-43 proteinopathy in amyotrophic lateral sclerosis
title Distinct responses of neurons and astrocytes to TDP-43 proteinopathy in amyotrophic lateral sclerosis
title_full Distinct responses of neurons and astrocytes to TDP-43 proteinopathy in amyotrophic lateral sclerosis
title_fullStr Distinct responses of neurons and astrocytes to TDP-43 proteinopathy in amyotrophic lateral sclerosis
title_full_unstemmed Distinct responses of neurons and astrocytes to TDP-43 proteinopathy in amyotrophic lateral sclerosis
title_short Distinct responses of neurons and astrocytes to TDP-43 proteinopathy in amyotrophic lateral sclerosis
title_sort distinct responses of neurons and astrocytes to tdp-43 proteinopathy in amyotrophic lateral sclerosis
topic Reports
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7009461/
https://www.ncbi.nlm.nih.gov/pubmed/32040555
http://dx.doi.org/10.1093/brain/awz419
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