N471D WASH complex subunit strumpellin knock-in mice display mild motor and cardiac abnormalities and BPTF and KLHL11 dysregulation in brain tissue

  • Aims: We investigated N471D WASH complex subunit strumpellin (Washc5) knock-in and Washc5 knock-out mice as models for hereditary spastic paraplegia type 8 (SPG8). Methods: We generated heterozygous and homozygous N471D Washc5 knock-in mice and subjected them to a comprehensive clinical, morphological and laboratory parameter screen, and gait analyses. Brain tissue was used for proteomic analysis. Furthermore, we generated heterozygous Washc5 knock-out mice. WASH complex subunit strumpellin expression was determined by qPCR and immunoblotting. Results: Homozygous N471D Washc5 knock-in mice showed mild dilated cardiomyopathy, decreased acoustic startle reactivity, thinner eye lenses, increased alkaline phosphatase and potassium levels and increased white blood cell counts. Gait analyses revealed multiple aberrations indicative of locomotor instability. Similarly, the clinical chemistry, haematology and gait parameters of heterozygous mice also deviated from the values expected for healthy animals, albeit to a lesser extent. Proteomic analysis of brain tissue depicted consistent upregulation of BPTF and downregulation of KLHL11 in heterozygous and homozygous knock-in mice. WASHC5-related protein interaction partners and complexes showed no change in abundancies. Heterozygous Washc5 knock-out mice showing normal WASHC5 levels could not be bred to homozygosity. Conclusions: While biallelic ablation of Washc5 was prenatally lethal, expression of N471D mutated WASHC5 led to several mild clinical and laboratory parameter abnormalities, but not to a typical SPG8 phenotype. The consistent upregulation of BPTF and downregulation of KLHL11 suggest mechanistic links between the expression of N471D mutated WASHC5 and the roles of both proteins in neurodegeneration and protein quality control, respectively.
Metadaten
Author:Christoph Stephan Clemen, Andreas Schmidt, Lilli Winter, Fabio Canneva, Ilka WittigORCiD, Lore Becker, Roland Coras, Carolin Berwanger, Andreas Hofmann, Britta Eggers, Katrin Marcus, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabe de Angelis, Marcus Krüger, Stephan von Hörsten, Ludwig Eichinger, Rolf Schröder
URN:urn:nbn:de:hebis:30:3-639530
DOI:https://doi.org/10.1111/nan.12750
ISSN:1365-2990
Parent Title (English):Neuropathology & applied neurobiology
Publisher:Wiley-Blackwell
Place of publication:Oxford [u.a.]
Document Type:Article
Language:English
Date of Publication (online):2021/07/27
Date of first Publication:2021/07/27
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Contributing Corporation:The German Mouse Clinic Consortium
Release Date:2022/04/19
Tag:BPTF; HSP (hereditary spastic paraplegia); KLHL11; N471D strumpellin knock-in mice; NURF; SPG8; WASH complex subunit 5; strumpellin
Volume:48
Issue:1, art. e12750
Page Number:15
First Page:1
Last Page:15
Note:
I. W. was funded by the Deutsche Forschungsgemeinschaft (DFG) (FOR5046/P5) and by the Cardio Pulmonary Institute (CPI) of the DFG (EXC2026). MHdA was funded by the German Federal Ministry of Education and Research (Infrafrontier grant 01KX1012) and the German Center for Diabetes Research (DZD).
HeBIS-PPN:494737298
Institutes:Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0