Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models
Structural changes and neuropathology in the hypothalamus have been suggested to contribute to the non-motor manifestations of Huntington’s disease (HD), a neurodegenerative disorder caused by an expanded cytosine-adenine-guanine (CAG) repeat in the huntingtin (HTT) gene. In this study, we investiga...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2022.1027269/full |
| _version_ | 1798045606751502336 |
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| author | Elna Dickson Amoolya Sai Dwijesha Natalie Andersson Sofia Lundh Maria Björkqvist Åsa Petersén Rana Soylu-Kucharz |
| author_facet | Elna Dickson Amoolya Sai Dwijesha Natalie Andersson Sofia Lundh Maria Björkqvist Åsa Petersén Rana Soylu-Kucharz |
| author_sort | Elna Dickson |
| collection | DOAJ |
| description | Structural changes and neuropathology in the hypothalamus have been suggested to contribute to the non-motor manifestations of Huntington’s disease (HD), a neurodegenerative disorder caused by an expanded cytosine-adenine-guanine (CAG) repeat in the huntingtin (HTT) gene. In this study, we investigated whether hypothalamic HTT expression causes transcriptional changes. Hypothalamic RNA was isolated from two different HD mouse models and their littermate controls; BACHD mice with ubiquitous expression of full-length mutant HTT (mHTT) and wild-type mice with targeted hypothalamic overexpression of either wild-type HTT (wtHTT) or mHTT fragments. The mHTT and wtHTT groups showed the highest number of differentially expressed genes compared to the BACHD mouse model. Gene Set Enrichment Analysis (GSEA) with leading-edge analysis showed that suppressed sterol- and cholesterol metabolism were shared between hypothalamic wtHTT and mHTT overexpression. Most distinctive for mHTT overexpression was the suppression of neuroendocrine networks, in which qRT-PCR validation confirmed significant downregulation of neuropeptides with roles in feeding behavior; hypocretin neuropeptide precursor (Hcrt), tachykinin receptor 3 (Tacr3), cocaine and amphetamine-regulated transcript (Cart) and catecholamine-related biological processes; dopa decarboxylase (Ddc), histidine decarboxylase (Hdc), tyrosine hydroxylase (Th), and vasoactive intestinal peptide (Vip). In BACHD mice, few hypothalamic genes were differentially expressed compared to age-matched WT controls. However, GSEA indicated an enrichment of inflammatory- and gonadotropin-related processes at 10 months. In conclusion, we show that both wtHTT and mHTT overexpression change hypothalamic transcriptome profile, specifically mHTT, altering neuroendocrine circuits. In contrast, the ubiquitous expression of full-length mHTT in the BACHD hypothalamus moderately affects the transcriptomic profile. |
| first_indexed | 2024-04-11T23:23:45Z |
| format | Article |
| id | doaj.art-ced1aed2ba324772b881459b9328d9b9 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-04-11T23:23:45Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-ced1aed2ba324772b881459b9328d9b92022-12-22T03:57:23ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2022-11-011610.3389/fnins.2022.10272691027269Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse modelsElna Dickson0Amoolya Sai Dwijesha1Natalie Andersson2Sofia Lundh3Maria Björkqvist4Åsa Petersén5Rana Soylu-Kucharz6Biomarkers in Brain Disease, Department of Experimental Medical Science, Lund University, Lund, SwedenTranslational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, SwedenPathways of Cancer Cell Evolution, Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, SwedenTranslational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, SwedenBiomarkers in Brain Disease, Department of Experimental Medical Science, Lund University, Lund, SwedenTranslational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, SwedenBiomarkers in Brain Disease, Department of Experimental Medical Science, Lund University, Lund, SwedenStructural changes and neuropathology in the hypothalamus have been suggested to contribute to the non-motor manifestations of Huntington’s disease (HD), a neurodegenerative disorder caused by an expanded cytosine-adenine-guanine (CAG) repeat in the huntingtin (HTT) gene. In this study, we investigated whether hypothalamic HTT expression causes transcriptional changes. Hypothalamic RNA was isolated from two different HD mouse models and their littermate controls; BACHD mice with ubiquitous expression of full-length mutant HTT (mHTT) and wild-type mice with targeted hypothalamic overexpression of either wild-type HTT (wtHTT) or mHTT fragments. The mHTT and wtHTT groups showed the highest number of differentially expressed genes compared to the BACHD mouse model. Gene Set Enrichment Analysis (GSEA) with leading-edge analysis showed that suppressed sterol- and cholesterol metabolism were shared between hypothalamic wtHTT and mHTT overexpression. Most distinctive for mHTT overexpression was the suppression of neuroendocrine networks, in which qRT-PCR validation confirmed significant downregulation of neuropeptides with roles in feeding behavior; hypocretin neuropeptide precursor (Hcrt), tachykinin receptor 3 (Tacr3), cocaine and amphetamine-regulated transcript (Cart) and catecholamine-related biological processes; dopa decarboxylase (Ddc), histidine decarboxylase (Hdc), tyrosine hydroxylase (Th), and vasoactive intestinal peptide (Vip). In BACHD mice, few hypothalamic genes were differentially expressed compared to age-matched WT controls. However, GSEA indicated an enrichment of inflammatory- and gonadotropin-related processes at 10 months. In conclusion, we show that both wtHTT and mHTT overexpression change hypothalamic transcriptome profile, specifically mHTT, altering neuroendocrine circuits. In contrast, the ubiquitous expression of full-length mHTT in the BACHD hypothalamus moderately affects the transcriptomic profile.https://www.frontiersin.org/articles/10.3389/fnins.2022.1027269/fullHuntington’s diseaseneuroendocrinehypothalamusmicroarrayHD mouse modelshuntingtin |
| spellingShingle | Elna Dickson Amoolya Sai Dwijesha Natalie Andersson Sofia Lundh Maria Björkqvist Åsa Petersén Rana Soylu-Kucharz Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models Frontiers in Neuroscience Huntington’s disease neuroendocrine hypothalamus microarray HD mouse models huntingtin |
| title | Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models |
| title_full | Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models |
| title_fullStr | Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models |
| title_full_unstemmed | Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models |
| title_short | Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models |
| title_sort | microarray profiling of hypothalamic gene expression changes in huntington s disease mouse models |
| topic | Huntington’s disease neuroendocrine hypothalamus microarray HD mouse models huntingtin |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2022.1027269/full |
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