Mutant huntingtin confers cell-autonomous phenotypes on Huntington’s disease iPSC-derived microglia
Abstract Huntington’s disease (HD) is a neurodegenerative disorder caused by a dominantly inherited CAG repeat expansion in the huntingtin gene (HTT). Neuroinflammation and microglia have been implicated in HD pathology, however it has been unclear if mutant HTT (mHTT) expression has an adverse cell...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-11-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-46852-z |
| _version_ | 1797452853999042560 |
|---|---|
| author | Nina Stöberl Jasmine Donaldson Caroline S. Binda Branduff McAllister Hazel Hall-Roberts Lesley Jones Thomas H. Massey Nicholas D. Allen |
| author_facet | Nina Stöberl Jasmine Donaldson Caroline S. Binda Branduff McAllister Hazel Hall-Roberts Lesley Jones Thomas H. Massey Nicholas D. Allen |
| author_sort | Nina Stöberl |
| collection | DOAJ |
| description | Abstract Huntington’s disease (HD) is a neurodegenerative disorder caused by a dominantly inherited CAG repeat expansion in the huntingtin gene (HTT). Neuroinflammation and microglia have been implicated in HD pathology, however it has been unclear if mutant HTT (mHTT) expression has an adverse cell-autonomous effect on microglial function, or if they are only activated in response to the neurodegenerative brain environment in HD. To establish a human cell model of HD microglia function, we generated isogenic controls for HD patient-derived induced pluripotent stem cells (iPSC) with 109 CAG repeats (Q109). Q109 and isogenic Q22 iPSC, as well as non-isogenic Q60 and Q33 iPSC lines, were differentiated to iPSC-microglia. Our study supports a model of basal microglia dysfunction in HD leading to elevated pro-inflammatory cytokine production together with impaired phagocytosis and endocytosis capacity, in the absence of immune stimulation. These findings are consistent with early microglia activation observed in pre-manifest patients and indicate that mHTT gene expression affects microglia function in a cell-autonomous way. |
| first_indexed | 2024-03-09T15:14:40Z |
| format | Article |
| id | doaj.art-776cc0348ad24bafa0ac3a683d030c4d |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-09T15:14:40Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-776cc0348ad24bafa0ac3a683d030c4d2023-11-26T13:11:03ZengNature PortfolioScientific Reports2045-23222023-11-0113111510.1038/s41598-023-46852-zMutant huntingtin confers cell-autonomous phenotypes on Huntington’s disease iPSC-derived microgliaNina Stöberl0Jasmine Donaldson1Caroline S. Binda2Branduff McAllister3Hazel Hall-Roberts4Lesley Jones5Thomas H. Massey6Nicholas D. Allen7School of Biosciences, Cardiff UniversityCentre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff UniversityCentre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff UniversityCentre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff UniversityUK Dementia Research Institute at Cardiff, Cardiff UniversityCentre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff UniversityCentre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff UniversitySchool of Biosciences, Cardiff UniversityAbstract Huntington’s disease (HD) is a neurodegenerative disorder caused by a dominantly inherited CAG repeat expansion in the huntingtin gene (HTT). Neuroinflammation and microglia have been implicated in HD pathology, however it has been unclear if mutant HTT (mHTT) expression has an adverse cell-autonomous effect on microglial function, or if they are only activated in response to the neurodegenerative brain environment in HD. To establish a human cell model of HD microglia function, we generated isogenic controls for HD patient-derived induced pluripotent stem cells (iPSC) with 109 CAG repeats (Q109). Q109 and isogenic Q22 iPSC, as well as non-isogenic Q60 and Q33 iPSC lines, were differentiated to iPSC-microglia. Our study supports a model of basal microglia dysfunction in HD leading to elevated pro-inflammatory cytokine production together with impaired phagocytosis and endocytosis capacity, in the absence of immune stimulation. These findings are consistent with early microglia activation observed in pre-manifest patients and indicate that mHTT gene expression affects microglia function in a cell-autonomous way.https://doi.org/10.1038/s41598-023-46852-z |
| spellingShingle | Nina Stöberl Jasmine Donaldson Caroline S. Binda Branduff McAllister Hazel Hall-Roberts Lesley Jones Thomas H. Massey Nicholas D. Allen Mutant huntingtin confers cell-autonomous phenotypes on Huntington’s disease iPSC-derived microglia Scientific Reports |
| title | Mutant huntingtin confers cell-autonomous phenotypes on Huntington’s disease iPSC-derived microglia |
| title_full | Mutant huntingtin confers cell-autonomous phenotypes on Huntington’s disease iPSC-derived microglia |
| title_fullStr | Mutant huntingtin confers cell-autonomous phenotypes on Huntington’s disease iPSC-derived microglia |
| title_full_unstemmed | Mutant huntingtin confers cell-autonomous phenotypes on Huntington’s disease iPSC-derived microglia |
| title_short | Mutant huntingtin confers cell-autonomous phenotypes on Huntington’s disease iPSC-derived microglia |
| title_sort | mutant huntingtin confers cell autonomous phenotypes on huntington s disease ipsc derived microglia |
| url | https://doi.org/10.1038/s41598-023-46852-z |
| work_keys_str_mv | AT ninastoberl mutanthuntingtinconferscellautonomousphenotypesonhuntingtonsdiseaseipscderivedmicroglia AT jasminedonaldson mutanthuntingtinconferscellautonomousphenotypesonhuntingtonsdiseaseipscderivedmicroglia AT carolinesbinda mutanthuntingtinconferscellautonomousphenotypesonhuntingtonsdiseaseipscderivedmicroglia AT branduffmcallister mutanthuntingtinconferscellautonomousphenotypesonhuntingtonsdiseaseipscderivedmicroglia AT hazelhallroberts mutanthuntingtinconferscellautonomousphenotypesonhuntingtonsdiseaseipscderivedmicroglia AT lesleyjones mutanthuntingtinconferscellautonomousphenotypesonhuntingtonsdiseaseipscderivedmicroglia AT thomashmassey mutanthuntingtinconferscellautonomousphenotypesonhuntingtonsdiseaseipscderivedmicroglia AT nicholasdallen mutanthuntingtinconferscellautonomousphenotypesonhuntingtonsdiseaseipscderivedmicroglia |