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Ahulkenoids restore multiple phenotypes in vitro and in vivo in Myotonic Dystrophy type 1

ABSTRACT: Myotonic dystrophy type 1 is an autosomal dominant disorder without available treatment to slow or stop disease progression nowadays. It is clinically characterized by a progressive muscular weakness and multisystem degeneration. In this study, we characterized the impact of a new family of FKBP12 “reshapers” (known as ahulkenoids). Treatment with different ahulkenoids reversed the accumulation of oxidative stress, the impaired cell viability and proliferation as well as mitochondrial activity and metabolism defects in DM1 derived primary fibroblasts. Moreover, RNAseq analysis confirmed the restoration of molecular pathways related to cell cycle and cell metabolism. Importantly, treatment with ahulkenoids significantly maintained locomotor activity and extended lifespan of a Drosophila model of the DM1 disease. In summary, our results revealed the benefits of a new family of compounds, entitled ahulkenoids, in the pre-clinical setting of DM1

ORGANISM(S): Homo sapiens

PROVIDER: GSE186494 | GEO | 2024/12/19

REPOSITORIES: GEO

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Project description:Myotonic dystrophy type 1 (DM1) is a multisystem, autosomal-dominant inherited disorder caused by CTG microsatellite repeat expansions (MREs) in the 3’ untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene. Despite its prominence as the most common adult-onset muscular dystrophy, patients with congenital to juvenile-onset forms of DM1 can present with debilitating neurocognitive symptoms along the autism spectrum, characteristic of possible in utero cortical defects. However, the molecular mechanism by which CTG MREs lead to these developmental central nervous system (CNS) manifestations is unknown. Here, we showed that CUG foci discovered early in maturation of three-dimensional cortical organoids from DM1 patient-derived induced pluripotent stem cells, cause hyperphosphorylation of CUGBP Elav-Like Family Member 2 (CELF2 ) protein. Integrative single-cell RNA-seq and enhanced crosslinking and immunoprecipitation (eCLIP ) analysis revealed reduced CELF2 protein-RNA substrate interactions resulting in mis-regulation of genes critical for excitatory synaptic signaling in glutamatergic neurons, including key components of the Methyl-CpG binding protein 2 (MECP2) pathway. Comparisons to MECP2(-/-) cortical organoids revealed convergent molecular and cellular defects such as glutamate toxicity and neuronal loss. Our findings provide evidence suggesting that early-onset DM1 might involve neurodevelopmental disorder-associated pathways and identify N-Methyl-D-aspartic acid (NMDA ) antagonists as potential treatment avenues for neuronal defects in DM1. To determine if CUG expansions in DMPK alter cellular RNA composition during differentiation, we performed transcriptomic analyses using RNA-seq at four consecutive developmental stages, ranging from iPSCs to 6-month-old cortical organoids from two independent differentiations. mine We then performed gene expression profiling analysis using data obtained from RNA-seq of 4 different time points.

Project description:Myotonic dystrophy type 1 (DM1) is a multisystem, autosomal-dominant inherited disorder caused by CTG microsatellite repeat expansions (MREs) in the 3’ untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene. Despite its prominence as the most common adult-onset muscular dystrophy, patients with congenital to juvenile-onset forms of DM1 can present with debilitating neurocognitive symptoms along the autism spectrum, characteristic of possible in utero cortical defects. However, the molecular mechanism by which CTG MREs lead to these developmental central nervous system (CNS) manifestations is unknown. Here, we showed that CUG foci discovered early in maturation of three-dimensional cortical organoids from DM1 patient-derived induced pluripotent stem cells, cause hyperphosphorylation of CUGBP Elav-Like Family Member 2 (CELF2 ) protein. Integrative single-cell RNA-seq and enhanced crosslinking and immunoprecipitation (eCLIP ) analysis revealed reduced CELF2 protein-RNA substrate interactions resulting in mis-regulation of genes critical for excitatory synaptic signaling in glutamatergic neurons, including key components of the Methyl-CpG binding protein 2 (MECP2) pathway. Comparisons to MECP2(-/-) cortical organoids revealed convergent molecular and cellular defects such as glutamate toxicity and neuronal loss. Our findings provide evidence suggesting that early-onset DM1 might involve neurodevelopmental disorder-associated pathways and identify N-Methyl-D-aspartic acid (NMDA ) antagonists as potential treatment avenues for neuronal defects in DM1. To evaluate if the post-translational modification of CELF2 impacts its RNA targets, we generated transcriptome-wide eCLIP maps of CELF2 protein-RNA interactions in mature, 6-month-old control and DM1 cortical organoids. All CELF2 eCLIP libraries per organoid line were performed in biologically independent duplicates, with each replicate experiment consisting of a CELF2 (IP) and a paired size-matched input (SMInput) library . We used CLIPper to identify clusters of reads representing regions in the transcriptome significantly associated with CELF2 binding in both neurotypical lines and compared them to DM1 cortical organoids with 600 and 1200 CUG repeats.

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Ahulkenoids restore multiple phenotypes in vitro and in vivo in Myotonic Dystrophy type 1

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