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

Clemen, Christoph S. and Schmidt, Andreas and Winter, Lilli and Canneva, Fabio and Wittig, Ilka and Becker, Lore and Coras, Roland and Berwanger, Carolin and Hofmann, Andreas and Eggers, Britta and Marcus, Katrin and Gailus‐Durner, Valerie and Fuchs, Helmut and Hrabe de Angelis, Martin and Krüger, Marcus and Hörsten, Stephan and Eichinger, Ludwig and Schröder, Rolf (2021) N471D WASH complex subunit strumpellin knock‐in mice display mild motor and cardiac abnormalities and BPTF and KLHL11 dysregulation in brain tissue. Neuropathology and Applied Neurobiology, 48 (1), e12750. Wiley. doi: 10.1111/nan.12750. ISSN 0305-1846.

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Official URL: http://dx.doi.org/10.1111/nan.12750

Abstract

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

Item URL in elib:https://elib.dlr.de/144851/
Document Type:Article
Title:N471D WASH complex subunit strumpellin knock‐in mice display mild motor and cardiac abnormalities and BPTF and KLHL11 dysregulation in brain tissue
Authors:
AuthorsInstitution or Email of AuthorsAuthor's ORCID iD
Clemen, Christoph S.Christoph.Clemen (at) dlr.dehttps://orcid.org/0000-0002-1291-4219
Schmidt, AndreasUNSPECIFIEDUNSPECIFIED
Winter, LilliUNSPECIFIEDUNSPECIFIED
Canneva, FabioUNSPECIFIEDUNSPECIFIED
Wittig, IlkaUNSPECIFIEDUNSPECIFIED
Becker, LoreUNSPECIFIEDUNSPECIFIED
Coras, RolandUNSPECIFIEDUNSPECIFIED
Berwanger, CarolinCarolin.Berwanger (at) dlr.deUNSPECIFIED
Hofmann, AndreasUNSPECIFIEDUNSPECIFIED
Eggers, BrittaUNSPECIFIEDUNSPECIFIED
Marcus, KatrinUNSPECIFIEDUNSPECIFIED
Gailus‐Durner, ValerieUNSPECIFIEDUNSPECIFIED
Fuchs, HelmutUNSPECIFIEDUNSPECIFIED
Hrabe de Angelis, MartinUNSPECIFIEDUNSPECIFIED
Krüger, MarcusUNSPECIFIEDUNSPECIFIED
Hörsten, StephanUNSPECIFIEDUNSPECIFIED
Eichinger, LudwigUNSPECIFIEDUNSPECIFIED
Schröder, RolfUNSPECIFIEDUNSPECIFIED
Date:27 July 2021
Journal or Publication Title:Neuropathology and Applied Neurobiology
Refereed publication:Yes
Open Access:Yes
Gold Open Access:No
In SCOPUS:Yes
In ISI Web of Science:Yes
Volume:48
DOI :10.1111/nan.12750
Page Range:e12750
Publisher:Wiley
ISSN:0305-1846
Status:Published
Keywords:BPTF; HSP (hereditary spastic paraplegia); KLHL11; N471D strumpellin knock-in mice; NURF; SPG8; WASH complex subunit 5; strumpellin
HGF - Research field:Aeronautics, Space and Transport
HGF - Program:Space
HGF - Program Themes:Research under Space Conditions
DLR - Research area:Raumfahrt
DLR - Program:R FR - Research under Space Conditions
DLR - Research theme (Project):R - Muscle Mechanics and Metabolism
Location: Köln-Porz
Institutes and Institutions:Institute of Aerospace Medicine > Muscle and Bone Metabolism
Deposited By: Schönenberg, Sandra
Deposited On:28 Oct 2021 16:49
Last Modified:09 Feb 2022 13:38

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