ATM-deficiency induced microglial activation promotes neurodegeneration in Ataxia-Telangiectasia
Abstract WhileATMloss-of-function has long been identified as the genetic cause of Ataxia Telangiectasia (A-T), how this genetic mutation leads to selective and progressive degeneration of cerebellar Purkinje and granule neurons remains unclear.ATMexpression is enriched in microglia, the resident immune cell of the central nervous system, throughout cerebellar development and adulthood. Microglial activation has been strongly implicated in neurodegenerative disease and observed in rodent and cellular models ofATMdeficiency. Here, we find evidence of prominent inflammation of microglia in cerebellum from A-T patients using single-nucleus RNA-sequencing. A-T microglia have transcriptomic signatures of aging and neurodegenerative disease associated microglia. Pseudotime analysis revealed that activation of A-T microglia preceded upregulation of apoptosis related genes in granule and Purkinje neurons, and microglia exhibited increased neurotoxic cytokine signaling to granule and Purkinje neurons in A-T. To confirm these findings experimentally, we studied microglia and neurons that we generated from A-T patient vs. control induced pluripotent stem cells (iPSCs). Transcriptomic profiling of A-T iPSC-derived microglia revealed cell-intrinsic microglial activation of cytokine production and innate immune response pathways compared to controls. Furthermore, adding A-T microglia to co-cultures with either control or A-T iPSC-derived neurons was sufficient to induce cytotoxicity. Taken together, these studies reveal that cell-intrinsic microglial activation may play a critical role in the development and progression of neurodegeneration in Ataxia Telangiectasia..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 08. Nov. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lai, Jenny [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2021.09.09.459619 |
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| PPN (Katalog-ID): |
XBI032555725 |
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| 520 | |a Abstract WhileATMloss-of-function has long been identified as the genetic cause of Ataxia Telangiectasia (A-T), how this genetic mutation leads to selective and progressive degeneration of cerebellar Purkinje and granule neurons remains unclear.ATMexpression is enriched in microglia, the resident immune cell of the central nervous system, throughout cerebellar development and adulthood. Microglial activation has been strongly implicated in neurodegenerative disease and observed in rodent and cellular models ofATMdeficiency. Here, we find evidence of prominent inflammation of microglia in cerebellum from A-T patients using single-nucleus RNA-sequencing. A-T microglia have transcriptomic signatures of aging and neurodegenerative disease associated microglia. Pseudotime analysis revealed that activation of A-T microglia preceded upregulation of apoptosis related genes in granule and Purkinje neurons, and microglia exhibited increased neurotoxic cytokine signaling to granule and Purkinje neurons in A-T. To confirm these findings experimentally, we studied microglia and neurons that we generated from A-T patient vs. control induced pluripotent stem cells (iPSCs). Transcriptomic profiling of A-T iPSC-derived microglia revealed cell-intrinsic microglial activation of cytokine production and innate immune response pathways compared to controls. Furthermore, adding A-T microglia to co-cultures with either control or A-T iPSC-derived neurons was sufficient to induce cytotoxicity. Taken together, these studies reveal that cell-intrinsic microglial activation may play a critical role in the development and progression of neurodegeneration in Ataxia Telangiectasia. | ||
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| 700 | 1 | |a Kim, Junho |0 (orcid)0000-0003-3513-401X |4 aut | |
| 700 | 1 | |a Jeffries, Ailsa M. |0 (orcid)0000-0001-6233-4215 |4 aut | |
| 700 | 1 | |a Tolles, Allie |0 (orcid)0000-0002-5569-0710 |4 aut | |
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| 700 | 1 | |a Lodato, Michael A. |0 (orcid)0000-0003-4175-1073 |4 aut | |
| 700 | 1 | |a Lee, Eunjung Alice |0 (orcid)0000-0002-6574-9261 |4 aut | |
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