Neurodegenerative phosphoprotein signaling landscape in models of SCA3

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...

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Bibliographic Details
Published in:	Molecular brain 2021-03, Vol.14 (1), p.57-57, Article 57
Main Authors:	Sowa, Anna S, Popova, Taissia G, Harmuth, Tina, Weber, Jonasz J, Pereira Sena, Priscila, Schmidt, Jana, Hübener-Schmid, Jeannette, Schmidt, Thorsten
Format:	Article
Language:	eng
Subjects:	1-Phosphatidylinositol 3-kinase AKT protein Analysis Animal models Antibodies Apoptosis Ataxia Ataxin Ataxin-3 (ATXN3) DNA microarrays Embryo fibroblasts Fibroblasts Genetic engineering Intracellular signalling Kinases Machado-Joseph disease Machado-Joseph disease (MJD) Metabolic pathways Nervous system diseases Neurodegeneration Neurodegenerative diseases pERK Phosphorylation Plasmids Polyglutamine Protein arrays Proteins RPMA Signal transduction Software Spinocerebellar ataxia type 3 (SCA3) TOR protein Transcription Transgenic mice Trinucleotide repeat diseases
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Summary:	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.
ISSN:	1756-6606 1756-6606