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Clemen, C.S.* ; Schmidt, A.* ; Winter, L.* ; Canneva, F.* ; Wittig, I.* ; Becker, L. ; Coras, R.* ; Berwanger, C.* ; Hofmann, A.* ; Eggers, B.* ; Marcus, K.* ; Gailus-Durner, V. ; Fuchs, H. ; Hrabě de Angelis, M. ; Krüger, M.* ; von Hörsten, S.* ; Eichinger, L.* ; Schröder, R.* ; German Mouse Clinic Consortium (Aguilar-Pimentel, J.A. ; Schmidt-Weber, C.B. ; Treise, I. ; Spielmann, N. ; Amarie, O.V. ; Rozman, J. ; Garrett, L. ; Hölter, S.M. ; Wurst, W. ; Calzada-Wack, J. ; da Silva Buttkus, P. ; Rathkolb, B. ; Östereicher, M.A. ; Leuchtenberger, S. ; Stöger, C.) ; Maier, H.

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:e12750 (2022)
Open Access Green: Postprint online verfügbar 07/2022
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 hetero- 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 hetero- 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Bptf ; Hsp (hereditary Spastic Paraplegia) ; Klhl11 ; N471d Strumpellin Knock-in Mice ; Nurf ; Spg8 ; Strumpellin ; Wash Complex Subunit 5; Hereditary Spastic Paraplegia; Kiaa0196 Gene; Retromer; Mutation; Platform; Family; Neurons; Spg8
ISSN (print) / ISBN 0305-1846
e-ISSN 1365-2990
Quellenangaben Band: 48, Heft: 1, Seiten: , Artikelnummer: e12750 Supplement: ,
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Begutachtungsstatus Peer reviewed
Förderungen Cardio Pulmonary Institute
German Center for Diabetes Research
German Federal Ministry of Education and Research
Deutsche Forschungsgemeinschaft