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Mechanisms of aberrant splicing and its implication on RNA homeostasis in CAG expansion disorders

Subject Area Molecular Biology and Physiology of Neurons and Glial Cells
Term from 2019 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 417976764
 
Final Report Year 2024

Final Report Abstract

In recent years, the dogma of protein expression - 1 gene, to 1 mRNA (transcription and splicing), to 1 protein (translation) - has been questioned as a plethora of isoforms, i.e. alternatively spliced transcripts of the same gene, have been discovered. The family of CAG expansion diseases contains 9 diseases, including Huntington disease (HD). In these diseases, the elongated CAG tract leads to the appearance of elongated poly-glutamine (polyQ) domains in the mutant protein. These polyQ domains in turn lead to the formation of aggregates that bind other proteins and disrupt the cellular balance, ultimately leading to cell death. In recent publications, we were able to show that the HTT mRNA, the mutated gene in HD, is not completely spliced and a new isoform HTT1a is formed. This results in a very toxic HTT protein fragment that is only encoded by exon 1 and also contains the extended poly-glutamine domain. In this application, we investigated the underlying mechanisms of HTT1a generation in more detail, in particular the relationship between epigenetic regulation, transcription and alternative splicing in relation to HTT1a formation. Furthermore, in a very extensive analysis of human samples (more than 60 participants in the study), we were able to show via multiple 'omics data that disease-relevant intra-/inter-cellular signalling pathways are disturbed. Specifically, under this study, transcriptome and proteome datasets were generated and analysed from various tissues, as well as primary cell lines and induced pluripotent cells (iPSCs). Interestingly, we found that the regulation of extracellular vesicle biology is also dysregulated in HD patients, which led to a new DFG proposal. By further developing our expertise in RNA biology and bioinformatic analysis (third generation long-range sequencing, machine learning, coexpression networks, etc.), we were able to extend our analysis methods to another CAG disease (spinocerebellar ataxia 1), as well as beyond CAG diseases to retinal neurodegeneration. Current therapeutic approaches in HD include attempts to reduce the HTT mRNA. However, none of these therapeutic approaches have the ability to prevent the production of the toxic HTT1a fragment due to the localization of the target sequences. The experiments in our proposal contribute to a better understanding of the mechanisms responsible for the block in HTT mRNA splicing. This knowledge could help to develop specific therapeutic approaches that can specifically prevent the production of the toxic fragment.

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