Patient-derived three-dimensional cortical neurospheres to model Parkinson's disease.
There are currently no preventive or disease-modifying therapies for Parkinson's Disease (PD). Failures in clinical trials necessitate a re-evaluation of existing pre-clinical models in order to adopt systems that better recapitulate underlying disease mechanisms and better predict clinical out...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2022-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0277532 |
| _version_ | 1797956068058333184 |
|---|---|
| author | Waseem K Raja Esther Neves Christopher Burke Xin Jiang Ping Xu Kenneth J Rhodes Vikram Khurana Robert H Scannevin Chee Yeun Chung |
| author_facet | Waseem K Raja Esther Neves Christopher Burke Xin Jiang Ping Xu Kenneth J Rhodes Vikram Khurana Robert H Scannevin Chee Yeun Chung |
| author_sort | Waseem K Raja |
| collection | DOAJ |
| description | There are currently no preventive or disease-modifying therapies for Parkinson's Disease (PD). Failures in clinical trials necessitate a re-evaluation of existing pre-clinical models in order to adopt systems that better recapitulate underlying disease mechanisms and better predict clinical outcomes. In recent years, models utilizing patient-derived induced pluripotent stem cells (iPSC) have emerged as attractive models to recapitulate disease-relevant neuropathology in vitro without exogenous overexpression of disease-related pathologic proteins. Here, we utilized iPSC derived from patients with early-onset PD and dementia phenotypes that harbored either a point mutation (A53T) or multiplication at the α-synuclein/SNCA gene locus. We generated a three-dimensional (3D) cortical neurosphere culture model to better mimic the tissue microenvironment of the brain. We extensively characterized the differentiation process using quantitative PCR, Western immunoblotting and immunofluorescence staining. Differentiated and aged neurospheres revealed alterations in fatty acid profiles and elevated total and pathogenic phospho-α-synuclein levels in both A53T and the triplication lines compared to their isogenic control lines. Furthermore, treatment of the neurospheres with a small molecule inhibitor of stearoyl CoA desaturase (SCD) attenuated the protein accumulation and aberrant fatty acid profile phenotypes. Our findings suggest that the 3D cortical neurosphere model is a useful tool to interrogate targets for PD and amenable to test small molecule therapeutics. |
| first_indexed | 2024-04-10T23:44:08Z |
| format | Article |
| id | doaj.art-dc489e4bd46144f9b7df7448e27b06f6 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-10T23:44:08Z |
| publishDate | 2022-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-dc489e4bd46144f9b7df7448e27b06f62023-01-11T05:32:45ZengPublic Library of Science (PLoS)PLoS ONE1932-62032022-01-011712e027753210.1371/journal.pone.0277532Patient-derived three-dimensional cortical neurospheres to model Parkinson's disease.Waseem K RajaEsther NevesChristopher BurkeXin JiangPing XuKenneth J RhodesVikram KhuranaRobert H ScannevinChee Yeun ChungThere are currently no preventive or disease-modifying therapies for Parkinson's Disease (PD). Failures in clinical trials necessitate a re-evaluation of existing pre-clinical models in order to adopt systems that better recapitulate underlying disease mechanisms and better predict clinical outcomes. In recent years, models utilizing patient-derived induced pluripotent stem cells (iPSC) have emerged as attractive models to recapitulate disease-relevant neuropathology in vitro without exogenous overexpression of disease-related pathologic proteins. Here, we utilized iPSC derived from patients with early-onset PD and dementia phenotypes that harbored either a point mutation (A53T) or multiplication at the α-synuclein/SNCA gene locus. We generated a three-dimensional (3D) cortical neurosphere culture model to better mimic the tissue microenvironment of the brain. We extensively characterized the differentiation process using quantitative PCR, Western immunoblotting and immunofluorescence staining. Differentiated and aged neurospheres revealed alterations in fatty acid profiles and elevated total and pathogenic phospho-α-synuclein levels in both A53T and the triplication lines compared to their isogenic control lines. Furthermore, treatment of the neurospheres with a small molecule inhibitor of stearoyl CoA desaturase (SCD) attenuated the protein accumulation and aberrant fatty acid profile phenotypes. Our findings suggest that the 3D cortical neurosphere model is a useful tool to interrogate targets for PD and amenable to test small molecule therapeutics.https://doi.org/10.1371/journal.pone.0277532 |
| spellingShingle | Waseem K Raja Esther Neves Christopher Burke Xin Jiang Ping Xu Kenneth J Rhodes Vikram Khurana Robert H Scannevin Chee Yeun Chung Patient-derived three-dimensional cortical neurospheres to model Parkinson's disease. PLoS ONE |
| title | Patient-derived three-dimensional cortical neurospheres to model Parkinson's disease. |
| title_full | Patient-derived three-dimensional cortical neurospheres to model Parkinson's disease. |
| title_fullStr | Patient-derived three-dimensional cortical neurospheres to model Parkinson's disease. |
| title_full_unstemmed | Patient-derived three-dimensional cortical neurospheres to model Parkinson's disease. |
| title_short | Patient-derived three-dimensional cortical neurospheres to model Parkinson's disease. |
| title_sort | patient derived three dimensional cortical neurospheres to model parkinson s disease |
| url | https://doi.org/10.1371/journal.pone.0277532 |
| work_keys_str_mv | AT waseemkraja patientderivedthreedimensionalcorticalneurospherestomodelparkinsonsdisease AT estherneves patientderivedthreedimensionalcorticalneurospherestomodelparkinsonsdisease AT christopherburke patientderivedthreedimensionalcorticalneurospherestomodelparkinsonsdisease AT xinjiang patientderivedthreedimensionalcorticalneurospherestomodelparkinsonsdisease AT pingxu patientderivedthreedimensionalcorticalneurospherestomodelparkinsonsdisease AT kennethjrhodes patientderivedthreedimensionalcorticalneurospherestomodelparkinsonsdisease AT vikramkhurana patientderivedthreedimensionalcorticalneurospherestomodelparkinsonsdisease AT roberthscannevin patientderivedthreedimensionalcorticalneurospherestomodelparkinsonsdisease AT cheeyeunchung patientderivedthreedimensionalcorticalneurospherestomodelparkinsonsdisease |