Distinct responses of neurons and astrocytes to TDP-43 proteinopathy in amyotrophic lateral sclerosis
| Autor: | Emmanuel Risse, Phillip Smethurst, Jamie S. Mitchell, John Collinge, Giulia E. Tyzack, Jia Newcombe, Rickie Patani, Doaa M Taha, Katie Sidle, Yun-Ru Chen |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cytoplasm TDP-43 Cell Induced Pluripotent Stem Cells Biology Neuroprotection 03 medical and health sciences 0302 clinical medicine medicine Humans Amyotrophic lateral sclerosis oligomers Induced pluripotent stem cell Motor Neurons Cell Death Amyotrophic Lateral Sclerosis astrocytes aggregation Neurodegenerative Diseases Motor neuron medicine.disease Spinal cord DNA-Binding Proteins 030104 developmental biology medicine.anatomical_structure Spinal Cord Toxicity Neurology (clinical) Neuroscience 030217 neurology & neurosurgery Astrocyte Reports |
| Zdroj: | Brain |
| ISSN: | 1460-2156 |
| Popis: | Smethurst et al. develop a human, clinically relevant modelling platform that recapitulates key aspects of sporadic ALS. They demonstrate cell type-specific vulnerability to both seeded aggregation (induced by post-mortem tissue extracts) and upon treatment with highly purified recombinant TDP-43 oligomers. 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. |
| Databáze: | OpenAIRE |
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