Spinal cord extracts of amyotrophic lateral sclerosis spread TDP-43 pathology in cerebral organoids.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by progressive loss of motor neurons and there is currently no effective therapy. Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein 43 kDa (TDP-43) within the CNS is a pathological hallmark in spora...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-02-01
|
| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1010606 |
| _version_ | 1811158391421140992 |
|---|---|
| author | Yoshitaka Tamaki Jay P Ross Paria Alipour Charles-Étienne Castonguay Boting Li Helene Catoire Daniel Rochefort Makoto Urushitani Ryosuke Takahashi Joshua A Sonnen Stefano Stifani Patrick A Dion Guy A Rouleau |
| author_facet | Yoshitaka Tamaki Jay P Ross Paria Alipour Charles-Étienne Castonguay Boting Li Helene Catoire Daniel Rochefort Makoto Urushitani Ryosuke Takahashi Joshua A Sonnen Stefano Stifani Patrick A Dion Guy A Rouleau |
| author_sort | Yoshitaka Tamaki |
| collection | DOAJ |
| description | Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by progressive loss of motor neurons and there is currently no effective therapy. Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein 43 kDa (TDP-43) within the CNS is a pathological hallmark in sporadic ALS and prion-like propagation of pathogenic TDP-43 is thought to be implicated in disease progression. However, cell-to-cell transmission of pathogenic TDP-43 in the human CNS has not been confirmed experimentally. Here we used induced pluripotent stem cells (iPSCs)-derived cerebral organoids as recipient CNS tissue model that are anatomically relevant human brain. We injected postmortem spinal cord protein extracts individually from three non-ALS or five sporadic ALS patients containing pathogenic TDP-43 into the cerebral organoids to validate the templated propagation and spreading of TDP-43 pathology in human CNS tissue. We first demonstrated that the administration of spinal cord extracts from an ALS patient induced the formation of TDP-43 pathology that progressively spread in a time-dependent manner in cerebral organoids, suggesting that pathogenic TDP-43 from ALS functioned as seeds and propagated cell-to-cell to form de novo TDP-43 pathology. We also reported that the administration of ALS patient-derived protein extracts caused astrocyte proliferation to form astrogliosis in cerebral organoids, reproducing the pathological feature seen in ALS. Moreover, we showed pathogenic TDP-43 induced cellular apoptosis and that TDP-43 pathology correlated with genomic damage due to DNA double-strand breaks. Thus, our results provide evidence that patient-derived pathogenic TDP-43 can mimic the prion-like propagation of TDP-43 pathology in human CNS tissue. Our findings indicate that our assays with human cerebral organoids that replicate ALS pathophysiology have a promising strategy for creating readouts that could be used in future drug discovery efforts against ALS. |
| first_indexed | 2024-04-10T05:23:52Z |
| format | Article |
| id | doaj.art-95522895ecef4007a675cea94277e3f9 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-10T05:23:52Z |
| publishDate | 2023-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-95522895ecef4007a675cea94277e3f92023-03-08T05:31:02ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042023-02-01192e101060610.1371/journal.pgen.1010606Spinal cord extracts of amyotrophic lateral sclerosis spread TDP-43 pathology in cerebral organoids.Yoshitaka TamakiJay P RossParia AlipourCharles-Étienne CastonguayBoting LiHelene CatoireDaniel RochefortMakoto UrushitaniRyosuke TakahashiJoshua A SonnenStefano StifaniPatrick A DionGuy A RouleauAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by progressive loss of motor neurons and there is currently no effective therapy. Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein 43 kDa (TDP-43) within the CNS is a pathological hallmark in sporadic ALS and prion-like propagation of pathogenic TDP-43 is thought to be implicated in disease progression. However, cell-to-cell transmission of pathogenic TDP-43 in the human CNS has not been confirmed experimentally. Here we used induced pluripotent stem cells (iPSCs)-derived cerebral organoids as recipient CNS tissue model that are anatomically relevant human brain. We injected postmortem spinal cord protein extracts individually from three non-ALS or five sporadic ALS patients containing pathogenic TDP-43 into the cerebral organoids to validate the templated propagation and spreading of TDP-43 pathology in human CNS tissue. We first demonstrated that the administration of spinal cord extracts from an ALS patient induced the formation of TDP-43 pathology that progressively spread in a time-dependent manner in cerebral organoids, suggesting that pathogenic TDP-43 from ALS functioned as seeds and propagated cell-to-cell to form de novo TDP-43 pathology. We also reported that the administration of ALS patient-derived protein extracts caused astrocyte proliferation to form astrogliosis in cerebral organoids, reproducing the pathological feature seen in ALS. Moreover, we showed pathogenic TDP-43 induced cellular apoptosis and that TDP-43 pathology correlated with genomic damage due to DNA double-strand breaks. Thus, our results provide evidence that patient-derived pathogenic TDP-43 can mimic the prion-like propagation of TDP-43 pathology in human CNS tissue. Our findings indicate that our assays with human cerebral organoids that replicate ALS pathophysiology have a promising strategy for creating readouts that could be used in future drug discovery efforts against ALS.https://doi.org/10.1371/journal.pgen.1010606 |
| spellingShingle | Yoshitaka Tamaki Jay P Ross Paria Alipour Charles-Étienne Castonguay Boting Li Helene Catoire Daniel Rochefort Makoto Urushitani Ryosuke Takahashi Joshua A Sonnen Stefano Stifani Patrick A Dion Guy A Rouleau Spinal cord extracts of amyotrophic lateral sclerosis spread TDP-43 pathology in cerebral organoids. PLoS Genetics |
| title | Spinal cord extracts of amyotrophic lateral sclerosis spread TDP-43 pathology in cerebral organoids. |
| title_full | Spinal cord extracts of amyotrophic lateral sclerosis spread TDP-43 pathology in cerebral organoids. |
| title_fullStr | Spinal cord extracts of amyotrophic lateral sclerosis spread TDP-43 pathology in cerebral organoids. |
| title_full_unstemmed | Spinal cord extracts of amyotrophic lateral sclerosis spread TDP-43 pathology in cerebral organoids. |
| title_short | Spinal cord extracts of amyotrophic lateral sclerosis spread TDP-43 pathology in cerebral organoids. |
| title_sort | spinal cord extracts of amyotrophic lateral sclerosis spread tdp 43 pathology in cerebral organoids |
| url | https://doi.org/10.1371/journal.pgen.1010606 |
| work_keys_str_mv | AT yoshitakatamaki spinalcordextractsofamyotrophiclateralsclerosisspreadtdp43pathologyincerebralorganoids AT jaypross spinalcordextractsofamyotrophiclateralsclerosisspreadtdp43pathologyincerebralorganoids AT pariaalipour spinalcordextractsofamyotrophiclateralsclerosisspreadtdp43pathologyincerebralorganoids AT charlesetiennecastonguay spinalcordextractsofamyotrophiclateralsclerosisspreadtdp43pathologyincerebralorganoids AT botingli spinalcordextractsofamyotrophiclateralsclerosisspreadtdp43pathologyincerebralorganoids AT helenecatoire spinalcordextractsofamyotrophiclateralsclerosisspreadtdp43pathologyincerebralorganoids AT danielrochefort spinalcordextractsofamyotrophiclateralsclerosisspreadtdp43pathologyincerebralorganoids AT makotourushitani spinalcordextractsofamyotrophiclateralsclerosisspreadtdp43pathologyincerebralorganoids AT ryosuketakahashi spinalcordextractsofamyotrophiclateralsclerosisspreadtdp43pathologyincerebralorganoids AT joshuaasonnen spinalcordextractsofamyotrophiclateralsclerosisspreadtdp43pathologyincerebralorganoids AT stefanostifani spinalcordextractsofamyotrophiclateralsclerosisspreadtdp43pathologyincerebralorganoids AT patrickadion spinalcordextractsofamyotrophiclateralsclerosisspreadtdp43pathologyincerebralorganoids AT guyarouleau spinalcordextractsofamyotrophiclateralsclerosisspreadtdp43pathologyincerebralorganoids |