A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development
Huntington’s disease (HD) is a lethal neurodegenerative disorder without efficient therapeutic options. The inefficient translation from preclinical and clinical research into clinical use is mainly attributed to the lack of (i) understanding of disease initiation, progression, and involved molecula...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/23/14763 |
| _version_ | 1797463162990100480 |
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| author | Jingyun Wu Luisa Möhle Thomas Brüning Iván Eiriz Muhammad Rafehi Katja Stefan Sven Marcel Stefan Jens Pahnke |
| author_facet | Jingyun Wu Luisa Möhle Thomas Brüning Iván Eiriz Muhammad Rafehi Katja Stefan Sven Marcel Stefan Jens Pahnke |
| author_sort | Jingyun Wu |
| collection | DOAJ |
| description | Huntington’s disease (HD) is a lethal neurodegenerative disorder without efficient therapeutic options. The inefficient translation from preclinical and clinical research into clinical use is mainly attributed to the lack of (i) understanding of disease initiation, progression, and involved molecular mechanisms; (ii) knowledge of the possible HD target space and general data awareness; (iii) detailed characterizations of available disease models; (iv) better suitable models; and (v) reliable and sensitive biomarkers. To generate robust HD-like symptoms in a mouse model, the neomycin resistance cassette was excised from zQ175 mice, generating a new line: zQ175<sup>Δneo</sup>. We entirely describe the dynamics of behavioral, neuropathological, and immunohistological changes from 15–57 weeks of age. Specifically, zQ175<sup>Δneo</sup> mice showed early astrogliosis from 15 weeks; growth retardation, body weight loss, and anxiety-like behaviors from 29 weeks; motor deficits and reduced muscular strength from 36 weeks; and finally slight microgliosis at 57 weeks of age. Additionally, we collected the entire bioactivity network of small-molecule HD modulators in a multitarget dataset (HD_MDS). Hereby, we uncovered 358 unique compounds addressing over 80 different pharmacological targets and pathways. Our data will support future drug discovery approaches and may serve as useful assessment platform for drug discovery and development against HD. |
| first_indexed | 2024-03-09T17:46:46Z |
| format | Article |
| id | doaj.art-b6dd3dbb12864538b30e9438a0efd861 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T17:46:46Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b6dd3dbb12864538b30e9438a0efd8612023-11-24T11:07:29ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123231476310.3390/ijms232314763A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and DevelopmentJingyun Wu0Luisa Möhle1Thomas Brüning2Iván Eiriz3Muhammad Rafehi4Katja Stefan5Sven Marcel Stefan6Jens Pahnke7Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway; <uri>www.pahnkelab.eu</uri>Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway; <uri>www.pahnkelab.eu</uri>Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway; <uri>www.pahnkelab.eu</uri>Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway; <uri>www.pahnkelab.eu</uri>Institute of Clinical Pharmacology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, GermanyDepartment of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway; <uri>www.pahnkelab.eu</uri>Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway; <uri>www.pahnkelab.eu</uri>Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway; <uri>www.pahnkelab.eu</uri>Huntington’s disease (HD) is a lethal neurodegenerative disorder without efficient therapeutic options. The inefficient translation from preclinical and clinical research into clinical use is mainly attributed to the lack of (i) understanding of disease initiation, progression, and involved molecular mechanisms; (ii) knowledge of the possible HD target space and general data awareness; (iii) detailed characterizations of available disease models; (iv) better suitable models; and (v) reliable and sensitive biomarkers. To generate robust HD-like symptoms in a mouse model, the neomycin resistance cassette was excised from zQ175 mice, generating a new line: zQ175<sup>Δneo</sup>. We entirely describe the dynamics of behavioral, neuropathological, and immunohistological changes from 15–57 weeks of age. Specifically, zQ175<sup>Δneo</sup> mice showed early astrogliosis from 15 weeks; growth retardation, body weight loss, and anxiety-like behaviors from 29 weeks; motor deficits and reduced muscular strength from 36 weeks; and finally slight microgliosis at 57 weeks of age. Additionally, we collected the entire bioactivity network of small-molecule HD modulators in a multitarget dataset (HD_MDS). Hereby, we uncovered 358 unique compounds addressing over 80 different pharmacological targets and pathways. Our data will support future drug discovery approaches and may serve as useful assessment platform for drug discovery and development against HD.https://www.mdpi.com/1422-0067/23/23/14763Huntington’s diseaseneurodegenerationtherapydrug discoverydrug designABC transporters |
| spellingShingle | Jingyun Wu Luisa Möhle Thomas Brüning Iván Eiriz Muhammad Rafehi Katja Stefan Sven Marcel Stefan Jens Pahnke A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development International Journal of Molecular Sciences Huntington’s disease neurodegeneration therapy drug discovery drug design ABC transporters |
| title | A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development |
| title_full | A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development |
| title_fullStr | A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development |
| title_full_unstemmed | A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development |
| title_short | A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development |
| title_sort | novel huntington s disease assessment platform to support future drug discovery and development |
| topic | Huntington’s disease neurodegeneration therapy drug discovery drug design ABC transporters |
| url | https://www.mdpi.com/1422-0067/23/23/14763 |
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