TY  - JOUR
A1  - Clemen, Christoph Stephan
A1  - Schmidt, Andreas
A1  - Winter, Lilli
A1  - Canneva, Fabio
A1  - Wittig, Ilka
A1  - Becker, Lore
A1  - Coras, Roland
A1  - Berwanger, Carolin
A1  - Hofmann, Andreas
A1  - Eggers, Britta
A1  - Marcus, Katrin
A1  - Gailus-Durner, Valerie
A1  - Fuchs, Helmut
A1  - Hrabe de Angelis, Martin
A1  - Krüger, Marcus
A1  - Hörsten, Stephan von
A1  - Eichinger, Ludwig
A1  - Schröder, Rolf
T1  - N471D WASH complex subunit strumpellin knock-in mice display mild motor and cardiac abnormalities and BPTF and KLHL11 dysregulation in brain tissue
T2  - Neuropathology & applied neurobiology
N2  - 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.
KW  - N471D strumpellin knock-in mice
KW  - BPTF
KW  - HSP (hereditary spastic paraplegia)
KW  - KLHL11
KW  - NURF
KW  - SPG8
KW  - strumpellin
KW  - WASH complex subunit 5
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63953
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-639530
SN  - 1365-2990
N1  - 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).
VL  - 48
IS  - 1, art. e12750
SP  - 1
EP  - 15
PB  - Wiley-Blackwell
CY  - Oxford [u.a.]
ER  -