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

  • Smethurst, Phillip1, 2
  • Risse, Emmanuel3
  • Tyzack, Giulia E1, 2
  • Mitchell, Jamie S1, 2
  • Taha, Doaa M1, 2
  • Chen, Yun-Ru4
  • Newcombe, Jia5
  • Collinge, John3
  • Sidle, Katie1
  • Patani, Rickie1, 2
  • 1 Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
  • 2 The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
  • 3 MRC Prion Unit at UCL, UCL Institute of Prion Diseases, Courtauld Building, 33 Cleveland Street, London W1W 7FF.
  • 4 Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang District, Taipei 115, Taiwan. , (Taiwan)
  • 5 NeuroResource, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, 1 Wakefield Street, London, WC1N 1PJ, UK.
Published Article
Oxford University Press
Publication Date
Feb 01, 2020
DOI: 10.1093/brain/awz419
PMID: 32040555


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. © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.

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