Implications of Poly(A) Tail Processing in Repeat Expansion Diseases

Joachimiak, Paweł; Ciesiolka, Adam; Figura, Grzegorz; Fiszer, Agnieszka

doi:10.3390/cells11040677

Cited by 4 publications

(3 citation statements)

References 156 publications

(207 reference statements)

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“…The exact role of mutant transcripts in pathogenic mechanisms in polyQ diseases is being unraveled [10][11][12][13]. RNA-related studies have demonstrated so far: incomplete splicing of HTT mRNA [14], abnormal interactions of RNAs containing expanded CAG repeats with proteins [15,16], and RNA foci formation [17,18], and potential importance of alternative polyadenylation of various polyQ transcripts [19]. Furthermore, mutant polyQ disease transcripts have been shown to be promising therapeutic targets in strategies that aim to downregulate mutant gene expression [2,9,20].…”

Section: Introductionmentioning

confidence: 99%

Allele-specific quantitation of ATXN3 and HTT transcripts in polyQ disease models

et al. 2023

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Background The majority of genes in the human genome is present in two copies but the expression levels of both alleles is not equal. Allelic imbalance is an aspect of gene expression relevant not only in the context of genetic variation, but also to understand the pathophysiology of genes implicated in genetic disorders, in particular, dominant genetic diseases where patients possess one normal and one mutant allele. Polyglutamine (polyQ) diseases are caused by the expansion of CAG trinucleotide tracts within specific genes. Spinocerebellar ataxia type 3 (SCA3) and Huntington’s disease (HD) patients harbor one normal and one mutant allele that differ in the length of CAG tracts. However, assessing the expression level of individual alleles is challenging due to the presence of abundant CAG repeats in the human transcriptome, which make difficult the design of allele-specific methods, as well as of therapeutic strategies to selectively engage CAG sequences in mutant transcripts. Results To precisely quantify expression in an allele-specific manner, we used SNP variants that are linked to either normal or CAG expanded alleles of the ataxin-3 (ATXN3) and huntingtin (HTT) genes in selected patient-derived cell lines. We applied a SNP-based quantitative droplet digital PCR (ddPCR) protocol for precise determination of the levels of transcripts in cellular and mouse models. For HD, we showed that the process of cell differentiation can affect the ratio between endogenous alleles of HTT mRNA. Additionally, we reported changes in the absolute number of the ATXN3 and HTT transcripts per cell during neuronal differentiation. We also implemented our assay to reliably monitor, in an allele-specific manner, the silencing efficiency of mRNA-targeting therapeutic approaches for HD. Finally, using the humanized Hu128/21 HD mouse model, we showed that the ratio of normal and mutant HTT transgene expression in brain slightly changes with the age of mice. Conclusions Using allele-specific ddPCR assays, we observed differences in allele expression levels in the context of SCA3 and HD. Our allele-selective approach is a reliable and quantitative method to analyze low abundant transcripts and is performed with high accuracy and reproducibility. Therefore, the use of this approach can significantly improve understanding of allele-related mechanisms, e.g., related with mRNA processing that may be affected in polyQ diseases.

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Section: Introductionmentioning

confidence: 99%

Allele-specific quantitation of ATXN3 and HTT transcripts in polyQ disease models

et al. 2023

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“…It is rather a complicated network of effects of nuclear inclusions, mutant atrophin‐1 gain of function mechanisms resulting from increase in the number of its interactions, and transcription deregulation. There are other molecular mechanisms, already studied for other polyQ diseases, like RAN translation, 118,119 splicing deregulation, 120 or alternative polyadenylation 121 that should also be considered in the context of DRPLA.…”

Section: Future Perspectivesmentioning

confidence: 99%

Atrophin‐1 Function and Dysfunction in Dentatorubral–Pallidoluysian Atrophy

et al. 2023

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Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, incurable genetic disease that belongs to the group of polyglutamine (polyQ) diseases. DRPLA is the most common in the Japanese population; however, its global prevalence is also increasing due to better clinical recognition. It is characterized by cerebellar ataxia, myoclonus, epilepsy, dementia, and chorea. DRPLA is caused by dynamic mutation of CAG repeat expansion in ATN1 gene encoding the atrophin-1 protein. In the cascade of molecular disturbances, the pathological form of atrophin-1 is the initial factor, which has not been precisely characterized so far. Reports indicate that DRPLA is associated with disrupted protein-protein interactions (in which an expanded polyQ tract plays a crucial role), as well as gene expression deregulation. There is a great need to design efficient therapy that would address the underlying neurodegenerative process and thus prevent or alleviate DRPLA symptoms. An in-depth understanding of the normal atrophin-1 function and mutant atrophin-1 dysfunction is crucial for this purpose.

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“…Investigating mRNAs from genes implicated either in HD or spinocerebellar ataxia type 3 (SCA3) provides information about disproportions in allelic expression, as well as changes in expression levels during neuronal differentiation. This is a starting point for detailed analyses of mutant mRNA-specific processes (Ciesiolka et al, 2021 ; Joachimiak et al, 2022 ), which are important for a precise description of molecular mechanisms underlying polyQ diseases. In the last short talk in this session, Sambhavi Puri (Boston University School of Medicine, Boston, USA) shared the results on circRNAs deregulation in AD.…”

Section: Introductionmentioning

confidence: 99%

RNA regulation in brain function and disease 2022 (NeuroRNA): A conference report

Piwecka

Fiszer²,

Rolle³

et al. 2023

Front. Mol. Neurosci.

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Recent research integrates novel technologies and methods from the interface of RNA biology and neuroscience. This advancing integration of both fields creates new opportunities in neuroscience to deepen the understanding of gene expression programs and their regulation that underlies the cellular heterogeneity and physiology of the central nervous system. Currently, transcriptional heterogeneity can be studied in individual neural cell types in health and disease. Furthermore, there is an increasing interest in RNA technologies and their application in neurology. These aspects were discussed at an online conference that was shortly named NeuroRNA.

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Implications of Poly(A) Tail Processing in Repeat Expansion Diseases

Cited by 4 publications

References 156 publications

Allele-specific quantitation of ATXN3 and HTT transcripts in polyQ disease models

Allele-specific quantitation of ATXN3 and HTT transcripts in polyQ disease models

Atrophin‐1 Function and Dysfunction in Dentatorubral–Pallidoluysian Atrophy

RNA regulation in brain function and disease 2022 (NeuroRNA): A conference report

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