HNRNPA1-induced spliceopathy in a transgenic mouse model of myotonic dystrophy

Li, Moyi; Zhuang, Yan; Batra, Ranjan; Thomas, James; Li, Mao; Nutter, Curtis A.; Scotti, Marina M.; Carter, Helmut A.; Wang, Zhan Jun; Huang, Xusheng; Pu, Chuan Qiang; Swanson, Maurice S.; Xie, Wei

doi:10.1073/pnas.1907297117

Cited by 38 publications

(30 citation statements)

References 46 publications

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“…The functionally diverse heteronuclear ribonucleoprotein (hnRNP) family of RNA-binding proteins play key roles in RNA metabolism including mRNA stabilization and the regulation of alternative splicing ( Geuens et al., 2016 ; Martinez-Contreras et al., 2007 ). Genetic mutations and dysregulated expression of hnRNPs A1, E1/2 (PCBP1/2), I (PTBP1), P2 (FUS), and Q (SYNCRIP) are implicated in the molecular pathogenesis of neuromuscular disorders including myotonic and limb girdle muscular dystrophy, amyotrophic lateral sclerosis, and spinal muscle atrophy ( Geuens et al., 2016 ; Li et al., 2020 ; Vance et al., 2009 ). HnRNP family member U (hnRNP-U) is the largest member of the hnRNP family, ubiquitously expressed, and known to modulate both mRNA stability and alternative splicing ( Huelga et al., 2012 ; Xiao et al., 2012 ; Yugami et al., 2007 ).…”

Section: Introductionmentioning

confidence: 99%

Adult-Onset Myopathy with Constitutive Activation of Akt following the Loss of hnRNP-U

et al. 2020

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Summary Skeletal muscle has the remarkable ability to modulate its mass in response to changes in nutritional input, functional utilization, systemic disease, and age. This is achieved by the coordination of transcriptional and post-transcriptional networks and the signaling cascades balancing anabolic and catabolic processes with energy and nutrient availability. The extent to which alternative splicing regulates these signaling networks is uncertain. Here we investigate the role of the RNA-binding protein hnRNP-U on the expression and splicing of genes and the signaling processes regulating skeletal muscle hypertrophic growth. Muscle-specific Hnrnpu knockout (mKO) mice develop an adult-onset myopathy characterized by the selective atrophy of glycolytic muscle, the constitutive activation of Akt, increases in cellular and metabolic stress gene expression, and changes in the expression and splicing of metabolic and signal transduction genes. These findings link Hnrnpu with the balance between anabolic signaling, cellular and metabolic stress, and physiological growth.

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Section: Introductionmentioning

confidence: 99%

Adult-Onset Myopathy with Constitutive Activation of Akt following the Loss of hnRNP-U

et al. 2020

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“…However, this MBNL1‐ and CELF1‐centred view could be limiting our understanding of alternative splicing regulation in DM1. It was shown recently that another protein, heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), which is downregulated during normal postnatal development but remains upregulated in DM1, also induces fetal splicing defects in this disease (Li et al ., 2020). The overexpression of this protein in DM1 has a similar role to CELF1 in triggering muscle pathology, shifting splicing of DM1 RNA targets to an earlier developmental pattern.…”

Section: Cellular Processes Implicated In Dm1 Muscle Atrophymentioning

confidence: 99%

“…The overexpression of this protein in DM1 has a similar role to CELF1 in triggering muscle pathology, shifting splicing of DM1 RNA targets to an earlier developmental pattern. Interestingly, HNRNPA1 overexpression not only replicated DM1 splicing patterns in human myoblasts, but also revealed in HSA LR muscle that over 30% of targets overlapped with those of MBNL1 (Li et al ., 2020). Therefore, these data demonstrate that there is an imbalance of several key RNA‐binding proteins in splicing regulation, which also affect muscle differentiation in DM1.…”

Section: Cellular Processes Implicated In Dm1 Muscle Atrophymentioning

confidence: 99%

“…It has been shown that CELF1 and MBNL1 not only induce missplicing (see Section III.1), but can also alter other processes and structures, such as proteostasis (Timchenko, 2019), calcium regulation (Vallejo‐Illarramendi et al ., 2020) and sarcomere protein localisation (Llamusi et al ., 2013; Picchio et al ., 2018). Furthermore, there is evidence that supports a key role for other proteins that are affected by toxic CUG exp (Yadava et al ., 2008; Li et al ., 2020) and other processes that are altered in DM1 and could be contributing to the skeletal muscle phenotype (Thornell et al ., 2009; Zu et al ., 2010; Jones et al ., 2012; Cerro‐Herreros et al ., 2018; Sabater‐Arcis et al ., 2020).…”

Section: Introductionmentioning

confidence: 99%

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The hallmarks of myotonic dystrophy type 1 muscle dysfunction

et al. 2020

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Myotonic dystrophy type 1 (DM1) is the most prevalent form of muscular dystrophy in adults and yet there are currently no treatment options. Although this disease causes multisystemic symptoms, it is mainly characterised by myopathy or diseased muscles, which includes muscle weakness, atrophy, and myotonia, severely affecting the lives of patients worldwide. On a molecular level, DM1 is caused by an expansion of CTG repeats in the 3′ untranslated region (3′UTR) of the DM1 Protein Kinase (DMPK) gene which become pathogenic when transcribed into RNA forming ribonuclear foci comprised of auto complementary CUG hairpin structures that can bind proteins. This leads to the sequestration of the muscleblind‐like (MBNL) family of proteins, depleting them, and the abnormal stabilisation of CUGBP Elav‐like family member 1 (CELF1), enhancing it. Traditionally, DM1 research has focused on this RNA toxicity and how it alters MBNL and CELF1 functions as key splicing regulators. However, other proteins are affected by the toxic DMPK RNA and there is strong evidence that supports various signalling cascades playing an important role in DM1 pathogenesis. Specifically, the impairment of protein kinase B (AKT) signalling in DM1 increases autophagy, apoptosis, and ubiquitin–proteasome activity, which may also be affected in DM1 by AMP‐activated protein kinase (AMPK) downregulation. AKT also regulates CELF1 directly, by affecting its subcellular localisation, and indirectly as it inhibits glycogen synthase kinase 3 beta (GSK3β), which stabilises the repressive form of CELF1 in DM1. Another kinase that contributes to CELF1 mis‐regulation, in this case by hyperphosphorylation, is protein kinase C (PKC). Additionally, it has been demonstrated that fibroblast growth factor‐inducible 14 (Fn14) is induced in DM1 and is associated with downstream signalling through the nuclear factor κB (NFκB) pathways, associating inflammation with this disease. Furthermore, MBNL1 and CELF1 play a role in cytoplasmic processes involved in DM1 myopathy, altering proteostasis and sarcomere structure. Finally, there are many other elements that could contribute to the muscular phenotype in DM1 such as alterations to satellite cells, non‐coding RNA metabolism, calcium dysregulation, and repeat‐associated non‐ATG (RAN) translation. This review aims to organise the currently dispersed knowledge on the different pathways affected in DM1 and discusses the unexplored connections that could potentially help in providing new therapeutic targets in DM1 research.

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“…According to such a model, the numerous and different clinical manifestations in DM1 are determined by a reversion, in adult tissues, to fetal RNA processing patterns due to the increased expression of toxic CUG RNA expansions ( 8 ). The etiopathogenetic hypothesis most accredited to explain at the same time multisystem and high heterogeneity of DM1 is that of toxic RNA (“RNA toxic gain of function”).…”

Section: Introduction: the Complexity Of A Diseasementioning

confidence: 99%

Central Nervous System Involvement as Outcome Measure for Clinical Trials Efficacy in Myotonic Dystrophy Type 1

et al. 2020

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Increasing evidences indicate that in Myotonic Dystrophy type 1 (DM1 or Steinert disease), an autosomal dominant multisystem disorder caused by a (CTG)n expansion in DMPK gene on chromosome 19q13. 3, is the most common form of inherited muscular dystrophy in adult patients with a global prevalence of 1/8000, and involvement of the central nervous system can be included within the core clinical manifestations of the disease. Variable in its severity and progression rate over time, likely due to the underlying causative molecular mechanisms; this component of the clinical picture presents with high heterogeneity involving cognitive and behavioral alterations, but also sensory-motor neural integration, and in any case, significantly contributing to the disease burden projected to either specific functional neuropsychological domains or quality of life as a whole. Principle manifestations include alterations of the frontal lobe function, which is more prominent in patients with an early onset, such as in congenital and childhood onset forms, here associated with severe intellectual disabilities, speech and language delay and reduced IQ-values, while in adult onset DM1 cognitive and neuropsychological findings are usually not so severe. Different methods to assess central nervous system involvement in DM1 have then recently been developed, these ranging from more classical psychometric and cognitive functional instruments to sophisticated psycophysic, neurophysiologic and especially computerized neuroimaging techniques, in order to better characterize this disease component, at the same time underlining the opportunity to consider it a suitable marker on which measuring putative effectiveness of therapeutic interventions. This is the reason why, as outlined in the conclusive section of this review, the Authors are lead to wonder, perhaps in a provocative and even paradoxical way to arise the question, whether or not the myologist, by now the popular figure in charge to care of a patient with the DM1, needs to remain himself a neurologist to better appreciate, evaluate and speculate on this important aspect of Steinert disease.

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HNRNPA1-induced spliceopathy in a transgenic mouse model of myotonic dystrophy

Cited by 38 publications

References 46 publications

Adult-Onset Myopathy with Constitutive Activation of Akt following the Loss of hnRNP-U

Adult-Onset Myopathy with Constitutive Activation of Akt following the Loss of hnRNP-U

The hallmarks of myotonic dystrophy type 1 muscle dysfunction

Central Nervous System Involvement as Outcome Measure for Clinical Trials Efficacy in Myotonic Dystrophy Type 1

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