Novel aberrant genetic and epigenetic events in Friedreich׳s ataxia

Quesada, Mari Paz; Jones, Jimmy; Rodríguez‐Lozano, Francisco Javier; Moraleda, José Marı́a

doi:10.1016/j.yexcr.2015.04.013

Cited by 17 publications

(11 citation statements)

References 49 publications

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“…Taken together, these data indicate that miRNA-10a-5p is expressed in the nervous system, dysregulated in several neurological conditions, and confirmed to target BDNF, which is downregulated in neurodegeneration. On the other hand, Quesada et al observed an increase in BDNF expression in periodontal ligament cells of FRDA patients [28]. However, this is the only study, so far, which shows elevated expression levels of BDNF in a FRDA model.…”

Section: Discussionmentioning

confidence: 63%

“…Another study done using fibroblasts and lymphoblasts from FRDA patients indicated that miRNA-886-3p modulates FXN expression levels [27], which could potentially affect the severity of the FRDA phenotype. A follow-up study conducted in FRDA and control periodontal ligament cells demonstrated the opposite results, with miRNA-886-3p downregulated and miRNA-132 upregulated in FRDA cells [28], emphasizing the tissue/organ-related complexity of the miRNome. Subsequent studies on miRNA-886-3p reclassified this transcript as a significantly larger non-coding vault RNA transcribed by RNA polymerase III (vtRNA2-1, nc886) [29].…”

Section: Introductionmentioning

confidence: 95%

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A Comprehensive Transcriptome Analysis Identifies FXN and BDNF as Novel Targets of miRNAs in Friedreich’s Ataxia Patients

et al. 2020

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Friedreich's ataxia (FRDA) is a genetic neurodegenerative disease that is caused by guanine-adenine-adenine (GAA) nucleotide repeat expansions in the first intron of the frataxin (FXN) gene. Although present in the intron, this mutation leads to a substantial decrease in protein expression. Currently, no effective treatment is available for FRDA, and, in addition to FXN, other targets with therapeutic potential are continuously sought. As miRNAs can regulate the expression of a broad spectrum of genes, are used as biomarkers, and can serve as therapeutic tools, we decided to identify and characterize differentially expressed miRNAs and their targets in FRDA cells compared to unaffected control (CTRL) cells. In this study, we performed an integrated miRNAseq and RNAseq analysis using the same cohort of primary FRDA and CTRL cells. The results of the transcriptome studies were supported by bioinformatic analyses and validated by qRT-PCR. miRNA interactions with target genes were assessed by luciferase assays, qRT-PCR, and immunoblotting. In silico analysis identified the FXN transcript as a target of five miRNAs upregulated in FRDA cells. Further studies confirmed that miRNA-224-5p indeed targets FXN, resulting in decreases in mRNA and protein levels. We also validated the ability of miRNA-10a-5p to bind and regulate the levels of brain-derived neurotrophic factor (BDNF), an important modulator of neuronal growth. We observed a significant decrease in the levels of miRNA-10a-5p and increase in the levels of BDNF upon correction of FRDA cells via zinc-finger nuclease (ZFN)-mediated excision of expanded GAA repeats. Our comprehensive transcriptome analyses identified miRNA-224-5p and miRNA-10a-5p as negative regulators of the FXN and BDNF expression, respectively. These results emphasize not only the importance of miRNAs in the pathogenesis of FRDA but also their potential as therapeutic targets for this disease.

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 95%

A Comprehensive Transcriptome Analysis Identifies FXN and BDNF as Novel Targets of miRNAs in Friedreich’s Ataxia Patients

et al. 2020

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“…Although future research is required to optimize the diversity of in vitro neural induction protocols that have been designed for oral and dental stem cells [69], our results suggest that hPDLSCs could also be used as an in vitro human cell-based model for neurogenesis and neuronal polarization [37]. In addition, the easy procedure for obtaining these from adults in normal or pathological condictions, may represent, as we have demonstrated with periodontal ligament cells from children [70,71], a suitable way of developing in vitro cell models of human diseases.…”

Section: Discussionmentioning

confidence: 77%

Non-proliferative adult neurogenesis in neural crest-derived stem cells isolated from human periodontal ligament

Bueno

Martinez-Morga

2018

Preprint

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Self-renewal and lineage regulation of neural stem cells in the adult mammalian brain (aNSCs) are still far from been understood. Although previous studies have reported that some aNSCs in neurogenic niches showed irregular nuclei, their functional significance remains elusive. We used neural crest-derived human periodontal ligament stem cells (hPDLSCs) as an in vitro cell model of neurogenesis to investigate the functional significance of nuclear polymorphisms. Here, we show that hPDLSCs-derived neurons are not directly generated through cell division from stem cells. In fact, the cell shape of neural precursors is reset and start their neuronal development as round spheres. The hPDLSCs-derived neurons gradually adopted a complex morphology adquiring dendritic-like and axonal-like identities, giving rise to a variety of neuron-like morphologies. We have discovered a transient cell nuclei lobulation coincident to in vitro neurogenesis, without being related to cell proliferation. We observed that small DNA containing structures move within the cell and temporarily form lobed nuclei.Morphological analysis also reveals that neurogenic niches in the adult mouse brain contains cells with nuclear shapes highly similar to those observed during in vitro neurogenesis from hPDLSCs. Our results provide evidence that neuronal differentiation from aNSCs may also occur during in vivo adult mammalian neurogenesis without being related to cell proliferation. In addition, we demonstrate that hPDLSCs-derived neurons display a sequence of morphologic development highly similar to those observed in primary neuronal cultures derived from rodent brains during neurogenesis, providing evidence that it is possible to reproduce neurogenic processes and obtain neurons from hPDLSCs.

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“…These common genes, however, were uniquely enriched for genes involved in the regulation of apoptosis. Involvement of apoptotic mechanisms has been previously reported in FRDA cells (53,70,72,87,88). This suggests that to overcome the pitfalls of studies centered on iPSC-derived cell models, both multiple cell lines and isogenic lines are necessary.…”

Section: Discussionmentioning

confidence: 97%

Transcriptional profiling of isogenic Friedreich ataxia induced pluripotent stem cell-derived neurons

Lai¹,

Nachun²,

Petrosyan³

et al. 2018

Preprint

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Friedreich ataxia (FRDA) is a rare childhood neurodegenerative disorder with no effective treatment. FRDA is caused by transcriptional silencing of the FXN gene and consequent loss of the essential mitochondrial protein frataxin. Based on the knowledge that a GAA•TTC repeat expansion in the first intron of FXN leads to heterochromatin formation and gene silencing, we have shown that members of the 2-aminobenzamide family of histone deacetylase inhibitors (HDACi) reproducibly increase FXN mRNA levels in induced pluripotent stem cell (iPSC)derived FRDA neuronal cells and in peripheral blood mononuclear cells from patients treated with the drug in a phase I clinical trial. How the reduced expression of frataxin leads to neurological and other systemic symptoms in FRDA patients remains unclear. Similarly to other triplet repeat disorders, it is not known why only specific cells types are affected in the disease, primarily the large sensory neurons of the dorsal root ganglia and cardiomyocytes. The combination of iPSC technology and genome editing techniques offers the unique possibility of addressing these questions in a relevant cell model of the disease, without the confounding effect of different genetic backgrounds. We derived a set of isogenic iPSC lines that differ only in the length of the GAA•TTC repeats, using "scarless" gene-editing methods (helper-dependent adenovirus-mediated homologous recombination). To uncover the gene expression signature due to GAA•TTC repeat expansion in FRDA neuronal cells and the effect of HDACi on these changes, we performed transcriptomic analysis of iPSC-derived central nervous system (CNS)and isogenic sensory neurons by RNA sequencing. We find that multiple cellular pathways are commonly affected by the loss of frataxin in CNS and peripheral nervous system neurons and these changes are partially restored by HDACi treatment.

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Novel aberrant genetic and epigenetic events in Friedreich׳s ataxia

Cited by 17 publications

References 49 publications

A Comprehensive Transcriptome Analysis Identifies FXN and BDNF as Novel Targets of miRNAs in Friedreich’s Ataxia Patients

A Comprehensive Transcriptome Analysis Identifies FXN and BDNF as Novel Targets of miRNAs in Friedreich’s Ataxia Patients

Non-proliferative adult neurogenesis in neural crest-derived stem cells isolated from human periodontal ligament

Transcriptional profiling of isogenic Friedreich ataxia induced pluripotent stem cell-derived neurons

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