Myotonic dystrophy RNA toxicity alters morphology, adhesion and migration of mouse and human astrocytes

Dincã, Diana Mihaela; Lallemant, Louison; González-Barriga, Anchel; Cresto, Noémie; Bráz, Sandra; Sicot, Géraldine; Pillet, Laure-Elise; Polvèche, Hélène; Magneron, Paul; Huguet-Lachon, Aline; Benyamine, Hélène; Azotla-Vilchis, Cuauhtli N; Agonizantes-Juárez, Luis; Tahraoui-Boris, Julie; Martinat, Cécile; Hernández-Hernández, Óscar; Auboeuf, Didier; Rouach, Nathalie; Bourgeois, Cyril F.; Gourdon, Geneviève; Gomes‐Pereira, Mário

doi:10.1038/s41467-022-31594-9

Cited by 8 publications

(6 citation statements)

References 82 publications

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“…Astrocytes displayed abnormal morphology in the HIP after CRS ( Figure 3A ). The complexity of astrocytes processes was estimated by Sholl analysis, as previously described ( Dinca et al, 2022 ). The CRS mice showed fewer intersections in CA1 astrocytes compared with the Ctrl group, which was more significant in processes located 60–70 pixels from the nucleus ( Figures 3B, C, F ).…”

Section: Resultsmentioning

confidence: 99%

Astrocytes underlie a faster-onset antidepressant effect of hypidone hydrochloride (YL-0919)

Chang

et al. 2023

Front. Pharmacol.

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Introduction: Major depression disorder (MDD) is a common and potentially life-threatening mental illness; however, data on its pathogenesis and effective therapeutic measures are lacking. Pathological changes in astrocytes play a pivotal role in MDD. While hypidone hydrochloride (YL-0919), an independently developed antidepressant, has shown rapid action with low side effects, its underlying astrocyte-specific mechanisms remain unclear.Methods: In our study, mice were exposed to chronic restraint stress (CRS) for 14 days or concomitantly administered YL-0919/fluoxetine. Behavioral tests were applied to evaluate the depression model; immunofluorescence and immunohistochemistry staining were used to explore morphological changes in astrocytes; astrocyte-specific RNA sequencing (RNA-Seq) analysis was performed to capture transcriptome wide alterations; and ATP and oxygen consumption rate (OCR) levels of primary astrocytes were measured, followed by YL-0919 incubation to appraise the alteration of energy metabolism and mitochondrial oxidative phosphorylation (OXPHOS).Results: YL-0919 alleviated CRS-induced depressive-like behaviors faster than fluoxetine and attenuated the number and morphologic deficits in the astrocytes of depressed mice. The changes of gene expression profile in astrocytes after CRS were partially reversed by YL-0919. Moreover, YL-0919 improved astrocyte energy metabolism and mitochondrial OXPHOS in astrocytes.Conclusion: Our results provide evidence that YL-0919 exerted a faster-onset antidepressant effect on CRS-mice possibly via astrocyte structural remodeling and mitochondria functional restoration.

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Section: Resultsmentioning

confidence: 99%

Astrocytes underlie a faster-onset antidepressant effect of hypidone hydrochloride (YL-0919)

Chang

et al. 2023

Front. Pharmacol.

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“…First, the cell types vary between the GM and WM; neuronal cell bodies, protoplasmic astrocytes, and microglial cells are found primarily in the GM, while the WM includes axons, oligodendrocytes, fibrous astrocytes, microglial cells, and ependymal cells. In the DM1 brains, although the effects on non-neuronal cells remain unclear, RNA foci that astrocytes in the frontal cortex and hippocampus of mice are affected by CUG-RNA toxicity, and mis-splicing, which is observed in the astrocytes but not in the neurons, could be related to the functional defects in cell adhesion and spreading [34].…”

Section: Discussionmentioning

confidence: 98%

“…In the DM1 brains, although the effects on non-neuronal cells remain unclear, RNA foci accumulate in the astrocytes, oligodendrocytes, and neurons [32,33]. Dincã et al reported that astrocytes in the frontal cortex and hippocampus of mice are affected by CUG-RNA toxicity, and mis-splicing, which is observed in the astrocytes but not in the neurons, could be related to the functional defects in cell adhesion and spreading [34]. Accumulation of RNA foci and splicing abnormalities have also been reported in the oligodendrocytes of mice [35].…”

Section: Discussionmentioning

confidence: 99%

Analysis of splicing abnormalities in the white matter of myotonic dystrophy type 1 brain using RNA-sequence

Yoshizumi

Nishi

Igeta

et al. 2022

Preprint

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Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by the genomic expansions of CTG repeats, in which RNA-binding proteins, such as muscleblind-like protein, are sequestered in the nucleus, and abnormal splicing is observed in various genes. Although abnormal splicing reportedly occurs in the brains of patients with DM1, it is relation to the central nervous system symptoms is unknown. Several imaging studies have indicated substantial white matter (WM) defects in patients with DM1. Here, we performed RNA-sequencing and analysis of CTG repeat lengths in the frontal lobe of patients with DM1, separating the grey matter (GM) and WM, to investigate the splicing abnormalities in the DM1 brain, especially in the WM. The results demonstrated the number of repeats in the GM tended to be increase, with several genes showing similar levels of splicing abnormalities in the GM and WM, suggesting that the WM defects in DM1 are not only caused by aberrant splicing of GM RNA but also of WM RNA, which could be attributed to abnormal splicing of glial cell RNAs.

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“…Several functional consequences of MBNL1 and MAPT mis-splicing in MIO-M1 cells can be anticipated. Recently, MBNL-dependent splicing defects affecting mRNAs that control cell adhesion and spreading have been reported in DM1 astrocytes [ 51 ]. It has been described that MBNL1 exon 7 is necessary for MBNL dimerization and regulation of mRNAs involved in cell migration and DNA repair [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

RNA Foci Formation in a Retinal Glial Model for Spinocerebellar Ataxia Type 7

Suárez-Sánchez

Ávila-Avilés

Sanchez-Celis

et al. 2022

Life

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Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder characterized by cerebellar ataxia and retinopathy. SCA7 is caused by a CAG expansion in the ATXN7 gene, which results in an extended polyglutamine (polyQ) tract in the encoded protein, the ataxin-7. PolyQ expanded ataxin-7 elicits neurodegeneration in cerebellar Purkinje cells, however, its impact on the SCA7-associated retinopathy remains to be addressed. Since Müller glial cells play an essential role in retinal homeostasis, we generate an inducible model for SCA7, based on the glial Müller MIO-M1 cell line. The SCA7 pathogenesis has been explained by a protein gain-of-function mechanism, however, the contribution of the mutant RNA to the disease cannot be excluded. In this direction, we found nuclear and cytoplasmic foci containing mutant RNA accompanied by subtle alternative splicing defects in MIO-M1 cells. RNA foci were also observed in cells from different lineages, including peripheral mononuclear leukocytes derived from SCA7 patient, suggesting that this molecular mark could be used as a blood biomarker for SCA7. Collectively, our data showed that our glial cell model exhibits the molecular features of SCA7, which makes it a suitable model to study the RNA toxicity mechanisms, as well as to explore therapeutic strategies aiming to alleviate glial dysfunction.

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Myotonic dystrophy RNA toxicity alters morphology, adhesion and migration of mouse and human astrocytes

Cited by 8 publications

References 82 publications

Astrocytes underlie a faster-onset antidepressant effect of hypidone hydrochloride (YL-0919)

Astrocytes underlie a faster-onset antidepressant effect of hypidone hydrochloride (YL-0919)

Analysis of splicing abnormalities in the white matter of myotonic dystrophy type 1 brain using RNA-sequence

RNA Foci Formation in a Retinal Glial Model for Spinocerebellar Ataxia Type 7

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