Neurodegenerative phosphoprotein signaling landscape in models of SCA3.

Autor: Sowa AS; Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076, Tuebingen, Germany.; Centre for Rare Diseases, University of Tuebingen, 72076, Tuebingen, Germany., Popova TG; Center for Applied Proteomics and Molecular Medicine, College of Science, George Mason University, Manassas, VA, USA., Harmuth T; Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076, Tuebingen, Germany.; Centre for Rare Diseases, University of Tuebingen, 72076, Tuebingen, Germany., Weber JJ; Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076, Tuebingen, Germany.; Centre for Rare Diseases, University of Tuebingen, 72076, Tuebingen, Germany.; Department of Human Genetics, Ruhr-University Bochum, Universitaetsstrasse 150, 44801, Bochum, Germany., Pereira Sena P; Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076, Tuebingen, Germany.; Centre for Rare Diseases, University of Tuebingen, 72076, Tuebingen, Germany., Schmidt J; Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076, Tuebingen, Germany.; Centre for Rare Diseases, University of Tuebingen, 72076, Tuebingen, Germany., Hübener-Schmid J; Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076, Tuebingen, Germany.; Centre for Rare Diseases, University of Tuebingen, 72076, Tuebingen, Germany., Schmidt T; Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076, Tuebingen, Germany. Thorsten.Schmidt@med.uni-tuebingen.de.; Centre for Rare Diseases, University of Tuebingen, 72076, Tuebingen, Germany. Thorsten.Schmidt@med.uni-tuebingen.de.
Jazyk: angličtina
Zdroj: Molecular brain [Mol Brain] 2021 Mar 19; Vol. 14 (1), pp. 57. Date of Electronic Publication: 2021 Mar 19.
DOI: 10.1186/s13041-020-00723-0
Abstrakt: Spinocerebellar ataxia type 3 (SCA3) is a rare neurodegenerative disorder resulting from an aberrant expansion of a polyglutamine stretch in the ataxin-3 protein and subsequent neuronal death. The underlying intracellular signaling pathways are currently unknown. We applied the Reverse-phase Protein MicroArray (RPMA) technology to assess the levels of 50 signaling proteins (in phosphorylated and total forms) using three in vitro and in vivo models expressing expanded ataxin-3: (i) human embryonic kidney (HEK293T) cells stably transfected with human ataxin-3 constructs, (ii) mouse embryonic fibroblasts (MEF) from SCA3 transgenic mice, and (iii) whole brains from SCA3 transgenic mice. All three models demonstrated a high degree of similarity sharing a subset of phosphorylated proteins involved in the PI3K/AKT/GSK3/mTOR pathway. Expanded ataxin-3 strongly interfered (by stimulation or suppression) with normal ataxin-3 signaling consistent with the pathogenic role of the polyglutamine expansion. In comparison with normal ataxin-3, expanded ataxin-3 caused a pro-survival stimulation of the ERK pathway along with reduced pro-apoptotic and transcriptional responses.
Databáze: MEDLINE