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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Gespeichert in:

Autor*in:	Jingyun Wu [verfasserIn] Luisa Möhle [verfasserIn] Thomas Brüning [verfasserIn] Iván Eiriz [verfasserIn] Muhammad Rafehi [verfasserIn] Katja Stefan [verfasserIn] Sven Marcel Stefan [verfasserIn] Jens Pahnke [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	Huntington’s disease neurodegeneration therapy drug discovery drug design ABC transporters

Übergeordnetes Werk:	In: International Journal of Molecular Sciences - MDPI AG, 2003, 23(2022), 23, p 14763
Übergeordnetes Werk:	volume:23 ; year:2022 ; number:23, p 14763

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.3390/ijms232314763

Katalog-ID:	DOAJ025539825

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allfields	10.3390/ijms232314763 doi (DE-627)DOAJ025539825 (DE-599)DOAJb6dd3dbb12864538b30e9438a0efd861 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Jingyun Wu verfasserin aut A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Huntington’s disease neurodegeneration therapy drug discovery drug design ABC transporters Biology (General) Chemistry Luisa Möhle verfasserin aut Thomas Brüning verfasserin aut Iván Eiriz verfasserin aut Muhammad Rafehi verfasserin aut Katja Stefan verfasserin aut Sven Marcel Stefan verfasserin aut Jens Pahnke verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 23(2022), 23, p 14763 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:23 year:2022 number:23, p 14763 https://doi.org/10.3390/ijms232314763 kostenfrei https://doaj.org/article/b6dd3dbb12864538b30e9438a0efd861 kostenfrei https://www.mdpi.com/1422-0067/23/23/14763 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 23 2022 23, p 14763
spelling	10.3390/ijms232314763 doi (DE-627)DOAJ025539825 (DE-599)DOAJb6dd3dbb12864538b30e9438a0efd861 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Jingyun Wu verfasserin aut A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Huntington’s disease neurodegeneration therapy drug discovery drug design ABC transporters Biology (General) Chemistry Luisa Möhle verfasserin aut Thomas Brüning verfasserin aut Iván Eiriz verfasserin aut Muhammad Rafehi verfasserin aut Katja Stefan verfasserin aut Sven Marcel Stefan verfasserin aut Jens Pahnke verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 23(2022), 23, p 14763 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:23 year:2022 number:23, p 14763 https://doi.org/10.3390/ijms232314763 kostenfrei https://doaj.org/article/b6dd3dbb12864538b30e9438a0efd861 kostenfrei https://www.mdpi.com/1422-0067/23/23/14763 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 23 2022 23, p 14763
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allfieldsSound	10.3390/ijms232314763 doi (DE-627)DOAJ025539825 (DE-599)DOAJb6dd3dbb12864538b30e9438a0efd861 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Jingyun Wu verfasserin aut A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Huntington’s disease neurodegeneration therapy drug discovery drug design ABC transporters Biology (General) Chemistry Luisa Möhle verfasserin aut Thomas Brüning verfasserin aut Iván Eiriz verfasserin aut Muhammad Rafehi verfasserin aut Katja Stefan verfasserin aut Sven Marcel Stefan verfasserin aut Jens Pahnke verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 23(2022), 23, p 14763 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:23 year:2022 number:23, p 14763 https://doi.org/10.3390/ijms232314763 kostenfrei https://doaj.org/article/b6dd3dbb12864538b30e9438a0efd861 kostenfrei https://www.mdpi.com/1422-0067/23/23/14763 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 23 2022 23, p 14763
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author	Jingyun Wu
spellingShingle	Jingyun Wu misc QH301-705.5 misc QD1-999 misc Huntington’s disease misc neurodegeneration misc therapy misc drug discovery misc drug design misc ABC transporters misc Biology (General) misc Chemistry A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development
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title_auth	A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development
abstract	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.
abstractGer	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.
abstract_unstemmed	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.
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title_short	A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development
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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. 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