Author:
Gkekas Ioannis,Vagiona Aimilia-Christina,Pechlivanis Nikolaos,Kastrinaki Georgia,Pliatsika Katerina,Iben Sebastian,Xanthopoulos Konstantinos,Psomopoulos Fotis E.,Andrade-Navarro Miguel A.,Petrakis Spyros
Abstract
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by a trinucleotide (CAG) repeat expansion in the ATXN1 gene. It is characterized by the presence of polyglutamine (polyQ) intranuclear inclusion bodies (IIBs) within affected neurons. In order to investigate the impact of polyQ IIBs in SCA1 pathogenesis, we generated a novel protein aggregation model by inducible overexpression of the mutant ATXN1(Q82) isoform in human neuroblastoma SH-SY5Y cells. Moreover, we developed a simple and reproducible protocol for the efficient isolation of insoluble IIBs. Biophysical characterization showed that polyQ IIBs are enriched in RNA molecules which were further identified by next-generation sequencing. Finally, a protein interaction network analysis indicated that sequestration of essential RNA transcripts within ATXN1(Q82) IIBs may affect the ribosome resulting in error-prone protein synthesis and global proteome instability. These findings provide novel insights into the molecular pathogenesis of SCA1, highlighting the role of polyQ IIBs and their impact on critical cellular processes.
Funder
Hellenic Foundation for Research and Innovation
HORIZON EUROPE Widening participation and spreading excellence
Subject
Cellular and Molecular Neuroscience,Molecular Biology