Understanding the role of the hematopoietic niche in Huntington's disease's phenotypic expression: in vivo evidence using a parabiosis model
In a previous study, we have shown that parabiotic coupling of a knock-in mouse model (zQ175) of Huntington's disease (HD) to wild-type (WT) littermates resulted in a worsening of the normal phenotype as seen by detection of mutant huntingtin protein (mHTT) aggregates within peripheral organs a...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-05-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996123001055 |
| _version_ | 1827967731095306240 |
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| author | Marie Rieux Melanie Alpaugh Shireen Salem Alberto Siddu Martine Saint-Pierre Hélèna L. Denis Heike Rohweder Frank Herrmann Chantal Bazenet Steve Lacroix Francesca Cicchetti |
| author_facet | Marie Rieux Melanie Alpaugh Shireen Salem Alberto Siddu Martine Saint-Pierre Hélèna L. Denis Heike Rohweder Frank Herrmann Chantal Bazenet Steve Lacroix Francesca Cicchetti |
| author_sort | Marie Rieux |
| collection | DOAJ |
| description | In a previous study, we have shown that parabiotic coupling of a knock-in mouse model (zQ175) of Huntington's disease (HD) to wild-type (WT) littermates resulted in a worsening of the normal phenotype as seen by detection of mutant huntingtin protein (mHTT) aggregates within peripheral organs and the cerebral cortex as well as vascular abnormalities in WT mice. In contrast, parabiosis improved disease features in the zQ175 mice such as reduction of mHTT aggregate number in the liver and cortex, decrease in blood-brain barrier (BBB) permeability and attenuation of mitochondrial impairments. While the shared circulation mediated these effects, no specific factor was identified. To better understand which blood elements were involved in the aforementioned changes, WT and zQ175 mice underwent parabiotic surgery prior to exposing one of the paired animals to irradiation. The irradiation procedure successfully eliminated the hematopoietic niche followed by repopulation with cells originating from the non-irradiated parabiont, as measured by the quantification of mHTT levels in peripheral blood mononuclear cells. Although irradiation of the WT parabiont, causing the loss of healthy hematopoietic cells, did lead to a few alterations in mitochondrial function in the muscle (TOM40 levels), and increased neuroinflammation in the striatum (GFAP levels), most of the changes observed were likely attributable to the irradiation procedure itself (e.g. mHTT aggregates in cortex and liver; cellular stress in peripheral organs). However, factors such as mHTT aggregation in the brain and periphery, and BBB leakage, which were improved in zQ175 mice when paired to WT littermates in the previous parabiosis experiment, were unaffected by perturbation of the hematopoietic niche. It would therefore appear that cells of the hematopoietic stem cell niche are largely uninvolved in the beneficial effects of parabiosis. |
| first_indexed | 2024-04-09T18:09:30Z |
| format | Article |
| id | doaj.art-e49ceef186c14eb781f5cade28f1336a |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-04-09T18:09:30Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-e49ceef186c14eb781f5cade28f1336a2023-04-14T04:18:47ZengElsevierNeurobiology of Disease1095-953X2023-05-01180106091Understanding the role of the hematopoietic niche in Huntington's disease's phenotypic expression: in vivo evidence using a parabiosis modelMarie Rieux0Melanie Alpaugh1Shireen Salem2Alberto Siddu3Martine Saint-Pierre4Hélèna L. Denis5Heike Rohweder6Frank Herrmann7Chantal Bazenet8Steve Lacroix9Francesca Cicchetti10Centre de recherche du CHU de Québec – Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de médecine moléculaire, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, CanadaCentre de recherche du CHU de Québec – Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de psychiatrie & neurosciences, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, CanadaCentre de recherche du CHU de Québec – Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de médecine moléculaire, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, CanadaCentre de recherche du CHU de Québec – Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de psychiatrie & neurosciences, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, CanadaCentre de recherche du CHU de Québec – Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, CanadaCentre de recherche du CHU de Québec – Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de psychiatrie & neurosciences, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, CanadaEvotec SE, Essener Bogen 7, 22419 Hamburg, GermanyEvotec SE, Essener Bogen 7, 22419 Hamburg, GermanyEvotec SE, Essener Bogen 7, 22419 Hamburg, GermanyCentre de recherche du CHU de Québec – Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de médecine moléculaire, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, CanadaCentre de recherche du CHU de Québec – Université Laval, Axe neurosciences, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de médecine moléculaire, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, Canada; Département de psychiatrie & neurosciences, Université Laval, 1050 avenue de la Médecine, Québec, QC G1V 0A6, Canada; Corresponding author at: Centre de recherche du CHU de Québec – Université Laval, Axe Neurosciences, T2-07, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada.In a previous study, we have shown that parabiotic coupling of a knock-in mouse model (zQ175) of Huntington's disease (HD) to wild-type (WT) littermates resulted in a worsening of the normal phenotype as seen by detection of mutant huntingtin protein (mHTT) aggregates within peripheral organs and the cerebral cortex as well as vascular abnormalities in WT mice. In contrast, parabiosis improved disease features in the zQ175 mice such as reduction of mHTT aggregate number in the liver and cortex, decrease in blood-brain barrier (BBB) permeability and attenuation of mitochondrial impairments. While the shared circulation mediated these effects, no specific factor was identified. To better understand which blood elements were involved in the aforementioned changes, WT and zQ175 mice underwent parabiotic surgery prior to exposing one of the paired animals to irradiation. The irradiation procedure successfully eliminated the hematopoietic niche followed by repopulation with cells originating from the non-irradiated parabiont, as measured by the quantification of mHTT levels in peripheral blood mononuclear cells. Although irradiation of the WT parabiont, causing the loss of healthy hematopoietic cells, did lead to a few alterations in mitochondrial function in the muscle (TOM40 levels), and increased neuroinflammation in the striatum (GFAP levels), most of the changes observed were likely attributable to the irradiation procedure itself (e.g. mHTT aggregates in cortex and liver; cellular stress in peripheral organs). However, factors such as mHTT aggregation in the brain and periphery, and BBB leakage, which were improved in zQ175 mice when paired to WT littermates in the previous parabiosis experiment, were unaffected by perturbation of the hematopoietic niche. It would therefore appear that cells of the hematopoietic stem cell niche are largely uninvolved in the beneficial effects of parabiosis.http://www.sciencedirect.com/science/article/pii/S0969996123001055Huntington's diseaseParabiosisMutant huntingtin proteinzQ175IrradiationHematopoietic stem cells |
| spellingShingle | Marie Rieux Melanie Alpaugh Shireen Salem Alberto Siddu Martine Saint-Pierre Hélèna L. Denis Heike Rohweder Frank Herrmann Chantal Bazenet Steve Lacroix Francesca Cicchetti Understanding the role of the hematopoietic niche in Huntington's disease's phenotypic expression: in vivo evidence using a parabiosis model Neurobiology of Disease Huntington's disease Parabiosis Mutant huntingtin protein zQ175 Irradiation Hematopoietic stem cells |
| title | Understanding the role of the hematopoietic niche in Huntington's disease's phenotypic expression: in vivo evidence using a parabiosis model |
| title_full | Understanding the role of the hematopoietic niche in Huntington's disease's phenotypic expression: in vivo evidence using a parabiosis model |
| title_fullStr | Understanding the role of the hematopoietic niche in Huntington's disease's phenotypic expression: in vivo evidence using a parabiosis model |
| title_full_unstemmed | Understanding the role of the hematopoietic niche in Huntington's disease's phenotypic expression: in vivo evidence using a parabiosis model |
| title_short | Understanding the role of the hematopoietic niche in Huntington's disease's phenotypic expression: in vivo evidence using a parabiosis model |
| title_sort | understanding the role of the hematopoietic niche in huntington s disease s phenotypic expression in vivo evidence using a parabiosis model |
| topic | Huntington's disease Parabiosis Mutant huntingtin protein zQ175 Irradiation Hematopoietic stem cells |
| url | http://www.sciencedirect.com/science/article/pii/S0969996123001055 |
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