Thorsten Schmidt
Partner Thorsten Schmidt contributes to the field of Spinocerebellar ataxia type 3 since many years and e.g. generated one of the first antibodies against ataxin-3 (Schmidt et al., Brain Pathol, 1998) and contributed to the generation and characterization of animal models (e.g. Bichelmeier et al., J Neurosci, 2007; Boy et al., Hum Mol Genet, 2009). They recently observed, using mouse models for SCA3, that the nuclear localization of the affected protein ATXN3 is required for the manifestation of symptoms: ATXN3 (even with an extremely expanded polyglutamine repeat) remains harmless as long as the protein is kept in the cytoplasm. He further identified and characterized intracellular transport signals (two nuclear export signals, NES, and one nuclear localization signal, NLS) within the coding sequence of ATXN3 (Antony et al., Neurobiol Dis, 2009). Therefore, it is evident that proteins involved in the nucleocytoplasmic transport machinery recognize these localization signals, control the intracellular localization of ATXN3, thereby influence the toxicity and aggregation of ATXN3 and, thus, the pathogenesis of MJD.
The nuclear export of ATXN3 alleviates the phenotype. A) Immunohistochemical stainings of mice transgenic for ATXN3 with 148 glutamine repeats supplemented with an additional localization signal (NLS, NES) or without an additional signal (148). The aggregation rate is increased if ATXN3 is retained in the nucleus (using a nuclear localization signal, NLS). Keeping ATXN3 in the cytoplasm (using a nuclear export signal, NES), however, almost completely inhibits the aggregation of ATXN3. B) Footprint analyses revealed that the gait of mice with nuclear ATXN3 (NLS) is severely affected while mice with cytoplasmic ATXN3 (NES) exhibit an almost normal gait (Wild type).
References:
Antony PM, Mäntele S, Mollenkopf P, Boy J, Kehlenbach RH, Riess O, Schmidt T. "Identification and functional dissection of localization signals within ataxin-3", Neurobiol Dis. 2009 Nov;36(2):280-92. doi: 10.1016/j.nbd.2009.07.020. Epub 2009 Aug 4.
Bichelmeier U, Schmidt T, Hübener J, Boy J, Rüttiger L, Häbig K, Poths S, Bonin M, Knipper M, Schmidt WJ, Wilbertz J, Wolburg H, Laccone F, Riess O. "Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3: in vivo evidence", J Neurosci. 2007 Jul 11;27(28):7418-28.
Boy J, Schmidt T, Wolburg H, Mack A, Nuber S, Böttcher M, Schmitt I, Holzmann C, Zimmermann F, Servadio A, Riess O. "Reversibility of syndroms in a conditional mouse model of spinocerebellar ataxia type 3", Hum Mol Genet. 2009 Nov 15;18(22):4282-95. doi: 10.1093/hmg/ddp381. Epub 2009 Aug 10.
Schmidt T, Landwehrmeyer GB, Schmitt I, Trottier Y, Auburger G, Laccone F, Klockgether T, Völpel M, Epplen JT, Schöls L, Riess O. "An isoform of araxin-3 accumulates in the nucleus of neuronal cells in affected brain regions of SCA3 patients", Brain Pathol. 1998 Oct;8(4):669-79.