Clemen, Christoph S., Schmidt, Andreas, Winter, Lilli ORCID: 0000-0002-6368-1160, Canneva, Fabio, Wittig, Ilka, Becker, Lore, Coras, Roland, Berwanger, Carolin, Hofmann, Andreas ORCID: 0000-0003-4408-5467, Eggers, Britta, Marcus, Katrin, Gailus-Durner, Valerie, Fuchs, Helmut, de Angelis, Martin Hrabe ORCID: 0000-0002-7898-2353, Kruger, Marcus, von Horsten, Stephan, Eichinger, Ludwig and Schroder, Rolf (2022). N471D WASH complex subunit strumpellin knock-in mice display mild motor and cardiac abnormalities and BPTF and KLHL11 dysregulation in brain tissue. Neuropathol. Appl. Neurobiol., 48 (1). HOBOKEN: WILEY. ISSN 1365-2990

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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 Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Clemen, Christoph S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Winter, LilliUNSPECIFIEDorcid.org/0000-0002-6368-1160UNSPECIFIED
Canneva, FabioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wittig, IlkaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, LoreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coras, RolandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berwanger, CarolinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hofmann, AndreasUNSPECIFIEDorcid.org/0000-0003-4408-5467UNSPECIFIED
Eggers, BrittaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marcus, KatrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gailus-Durner, ValerieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fuchs, HelmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Angelis, Martin HrabeUNSPECIFIEDorcid.org/0000-0002-7898-2353UNSPECIFIED
Kruger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Horsten, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eichinger, LudwigUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schroder, RolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-600956
DOI: 10.1111/nan.12750
Journal or Publication Title: Neuropathol. Appl. Neurobiol.
Volume: 48
Number: 1
Date: 2022
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1365-2990
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HEREDITARY SPASTIC PARAPLEGIA; KIAA0196 GENE; RETROMER; MUTATION; PLATFORM; FAMILY; NEURONS; SPG8Multiple languages
Clinical Neurology; Neurosciences; PathologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60095

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