A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development
Year: 2022
Type: article
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: zQ175Δneo. We entirely describe the dynamics of behavioral, neuropathological, and immunohistological changes from 15–57 weeks of age. Specifically, zQ175Δneo 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.
Authors: Jingyun Wu, Luisa Möhle, Thomas Brüning, Iván Eiriz, Muhammad Rafehi, Katja Stefan, Sven Marcel Stefan, Jens Pahnke
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,408
Funders: EU Joint Programme – Neurodegenerative Disease Research, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Bundesministerium für Bildung und Forschung, Georg-August-Universität Göttingen, Österreichische Forschungsförderungsgesellschaft, Norges Forskningsråd, Nasjonalforeningen for Folkehelsen, Barnekreftforeningen, Helse Sør-Øst RHF, State Education Development Agency Republic of Latvia
Awards: G1054284181, G1178482883, G1243637826, G1244694202, G1352194028, G1470408927, G1489294876, PET analyses of ABC transporter function for diagnostics and stratification of dementia patients, G1567396479, Etablierung neuer Detektionsmethoden zur Entdeckung und Entwicklung neuer ABCA1 und ABCA7 Modulatoren als Alzheimer Therapeutika und Diagnostika, G1655068714, G1658402690, G1694600101, G1721423424, G1764706569, G1788821016, G1797662995, G1834835172, Untersuchungen zur Stereoselektivität von genetisch variablen Arzneistoffmembrantransportern der Solute Carrier Familie für ein besseres molekulares Verständnis und die Entwicklung sicherer Arzneimitteltherapien, G2050707350, G2229292916, G2420663071, G2513379724, G2593198994, G2601430393, Design, Synthese und biologische Bewertung von ABC TransporterAgonisten zur Entwicklung neuer Alzheimer Therapeutika, G2744681091, G2904944042, G2982210158, G3148790855, G3425763361, G3430797685, G349137744, G3541374072, G3638360959, G3765877793, G3877061302, G391668510, G4137409584, G4310662079, G436270212, G4409414385, G4460771976, G4464919134, G4477687095, G4486346275, G4591638188, Die Rolle der Blut Hirn Schranke in der Alzheimer Krankheit:
Untersuchung der funktionellen Interaktion von LRP1 mit ABCTransporterproteinen, G4813538387, G4817543206, G4892252235, G491704713, G5033494206, G5222996355, G5328352314, G5361889845, G5394259401, G5555565803, G5672552449, G5773812462, G5782635456, G5864106179, G5901861748, G5921906445, G5955346023, G5982436052, G6084469749, G6124491548, G6133652571, G6135628111, G6150325682, G6159004431, G6261811959, G6277749876, G6293138031, G6300611189, G6374517381, G6415745711, G6562291360, G6562485485, G6597822886, G6643041538, G6691255100, G6833900471, G6959673293, G6964618734, G7018064969, G7108348326, G7129013443, G7177051818, Exploration von PanABCTransporterModulatoren durch innovative In Silico und In Vitro Methoden zur Generierung potentieller Zielstrukturen, Diagnostika und Therapeutika, G7589017557, G7627239611, G7649966085, G7710459470, G7790086791, G7799852469, G8016496523, G8198015887, PETABC - PET-Untersuchungen der ABC-Transporterfunktion zur Diagnostik und Stratifizierung von Demenzpatienten, G824729715, G8453191506, G8468586087, G8550443092, G857078107, G865817754, G879137818, G965465959, G981964022, G998159348
OpenAlex ID: W4310244407