TY  - JOUR
AB  - 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.
AU  - Clemen, C.S.*
AU  - Schmidt, A.*
AU  - Winter, L.*
AU  - Canneva, F.*
AU  - Wittig, I.*
AU  - Becker, L.
AU  - Coras, R.*
AU  - Berwanger, C.*
AU  - Hofmann, A.*
AU  - Eggers, B.*
AU  - Marcus, K.*
AU  - Gailus-Durner, V.
AU  - Fuchs, H.
AU  - Hrabě de Angelis, M.
AU  - Krüger, M.*
AU  - von Hörsten, S.*
AU  - Eichinger, L.*
AU  - Schröder, R.*
AU  - German Mouse Clinic Consortium (Aguilar-Pimentel, J.A.
AU  - Schmidt-Weber, C.B.
AU  - Treise, I.
AU  - Spielmann, N.
AU  - Amarie, O.V.
AU  - Rozman, J.
AU  - Garrett, L.
AU  - Hölter, S.M.
AU  - Wurst, W.
AU  - Calzada-Wack, J.
AU  - da Silva Buttkus, P.
AU  - Rathkolb, B.
AU  - Östereicher, M.A.
AU  - Leuchtenberger, S.
AU  - Stoeger, C.)
AU  - Maier, H.
C1  - 62624
C2  - 50882
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - N471D WASH complex subunit strumpellin knock-in mice display mild motor and cardiac abnormalities and BPTF and KLHL11 dysregulation in brain tissue.
JO  - Neuropathol. Appl. Neurobiol.
VL  - 48
IS  - 1
PB  - Wiley
PY  - 2022
SN  - 0305-1846
ER  - 

TY  - JOUR
AB  - Aims: The aim of this study is to evaluate the pathological features, serum hormone levels and ex-vivo cultures of pituitary adenomas that occur in rats affected by MENX syndrome. MENX is multiple endocrine neoplasia syndrome caused by a germline mutation in the cell cycle inhibitor p27. Characterisation of MENX adenomas is a prerequisite to exploit this animal model for molecular and translational studies of pituitary adenomas. Methods: We investigated MENX pituitary adenomas with immunohistochemistry, double immunofluorescence, electron microscopy, RT-PCR, measurement of serum hormone levels and ex-vivo cultures. Results: Adenomas in MENX rats belong to the gonadotroph lineage. They start from 4 months of age as multiple neoplastic nodules and progress to become large lesions that efface the gland. Adenomas are composed of chromophobic cells predominantly expressing the glycoprotein alpha-subunit (αGSU). They show mitotic activity and high Ki67 labelling. A few neoplastic cells co-express gonadotrophins and the transcription factor SF1, together with growth hormone or prolactin and Pit-1, suggesting that they are not fully committed to one cell lineage. Ex vivo cultures show features similar to the primary tumour. Conclusions: Our results suggest that p27 function is critical in regulating gonadotroph cells growth. The MENX syndrome represents a unique model to elucidate the physiological and molecular mechanisms mediating the pathogenesis of gonadotroph adenomas.  
AU  - Marinoni, I.
AU  - Lee, M.S.
AU  - Mountford, S.
AU  - Perren, A.*
AU  - Bravi, I.*
AU  - Jennen, L.
AU  - Feuchtinger, A.
AU  - Drouin, J.*
AU  - Roncaroli, F.*
AU  - Pellegata, N.S.
C1  - 11667
C2  - 30740
SP  - 256-269
TI  - Characterization of MENX-associated pituitary tumours.
JO  - Neuropathol. Appl. Neurobiol.
VL  - 39
IS  - 3
PB  - Wiley-Blackwell
PY  - 2013
SN  - 0305-1846
ER  - 

TY  - JOUR
AU  - Anderson, C.E.*
AU  - Tomlinson, G.S.*
AU  - Pauly, B.
AU  - Brannan, F.W.*
AU  - Chiswick, A.*
AU  - Brack-Werner, R.
AU  - Simmonds, P.*
AU  - Bell, J.E.*
C1  - 22274
C2  - 21047
SP  - 378-388
TI  - Relationship of Nef-positive and GFAP-reactive astrocytes to drug use in early and late HIV  infection.
JO  - Neuropathol. Appl. Neurobiol.
VL  - 29
PY  - 2003
SN  - 0305-1846
ER  -