Perturbation of the Akt/Gsk3-β signalling pathway is common to Drosophila expressing expanded untranslated CAG, CUG and AUUCU repeat RNAs

Eyk, Clare L. van; O’Keefe, Louise V.; Lawlor, Kynan T.; Samaraweera, Saumya E.; McLeod, Catherine J.; Price, Gareth; Venter, Deon J.; Richards, Robert I.

doi:10.1093/hmg/ddr177

Cited by 29 publications

(25 citation statements)

References 64 publications

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“…This conclusion was made based on studies of two DM1 models: HSA LR mice, expressing CUG repeats in the 3′ UTR of skeletal muscle actin; and CHO double-stable clones expressing Tet-regulated pure CUG repeats. In agreement with our findings, a recent study has shown disruption of AKT/GSK3β signaling in neuronal cells in response to the expression of CUG repeats (40).…”

Section: Discussionsupporting

confidence: 94%

GSK3β mediates muscle pathology in myotonic dystrophy

Jones¹,

Wei²,

Iakova³

et al. 2012

J. Clin. Invest.

105

174

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Myotonic dystrophy type 1 (DM1) is a complex neuromuscular disease characterized by skeletal muscle wasting, weakness, and myotonia. DM1 is caused by the accumulation of CUG repeats, which alter the biological activities of RNA-binding proteins, including CUG-binding protein 1 (CUGBP1). CUGBP1 is an important skeletal muscle translational regulator that is activated by cyclin D3-dependent kinase 4 (CDK4). Here we show that mutant CUG repeats suppress Cdk4 signaling by increasing the stability and activity of glycogen synthase kinase 3β (GSK3β). Using a mouse model of DM1 (HSA LR ), we found that CUG repeats in the 3′ untranslated region (UTR) of human skeletal actin increase active GSK3β in skeletal muscle of mice, prior to the development of skeletal muscle weakness. Inhibition of GSK3β in both DM1 cell culture and mouse models corrected cyclin D3 levels and reduced muscle weakness and myotonia in DM1 mice. Our data predict that compounds normalizing GSK3β activity might be beneficial for improvement of muscle function in patients with DM1. IntroductionMyotonic dystrophy type 1 (DM1) is a complex disease affecting primarily skeletal muscle, causing myotonia, skeletal muscle weakness, and wasting (1). DM1 is caused by the expansion of polymorphic, noncoding CTG repeats in the 3′ untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) gene (2, 3). The severity of DM1 correlates with the length of CTG expansions. The longest CTG expansions are observed in patients with a congenital form of DM1 that affects newborn children (1). Congenital DM1 is characterized by a delay in skeletal muscle development, leading to extreme muscle weakness and a weak respiratory system, which has been associated with a high mortality rate (4, 5). Expanded CTG repeats cause the disease through RNA CUG repeats that misregulate several CUG RNA-binding proteins, including CUGBP1 (CUGBP Elav-like family member 1, CELF1) and muscleblind 1 (MBNL1) (6-24). The mutant CUG aggregates sequester MBNL1, reducing splicing of MBNL1-regulated mRNAs (11,12,17). A portion of the mutant CUG repeats bind to CUGBP1 and elevate CUGBP1 protein levels through an increase in its stability (14). Phosphorylation of CUGBP1 by PKC also contributes to the increase in CUGBP1 stability (24).CUGBP1 is a highly conserved, multifunctional protein that regulates RNA processing on several levels, including translation, RNA stability, and splicing (9, 14-16, 18, 20-22, 25-32). The increase in CUGBP1 to the levels observed in the congenital DM1 leads to the delay of myogenesis in the CUGBP1 transgenic mouse model (18). Multiple functions of CUGBP1 are tightly regulated by phosphorylation at distinct sites (21,22,24). Phosphorylation of CUGBP1 by AKT at S28 controls nucleus-cytoplasm distribution of CUGBP1 and increases CUGBP1 affinity toward certain mRNA targets (21,22). Translational activity of CUGBP1 is regulated by cyclin D3/CDK4 phosphorylation at S302 (21,22,29,32).

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Section: Discussionsupporting

confidence: 94%

GSK3β mediates muscle pathology in myotonic dystrophy

Jones¹,

Wei²,

Iakova³

et al. 2012

J. Clin. Invest.

105

174

View full text Add to dashboard Cite

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“…Where expanded repeats are translated, they generally code for polyglutamine; however, the proteins in which they are located are all unrelated in the remainder of their amino-acid sequence. Therefore, much attention has been focused on expanded polyglutamine as the common basis of pathology (McLeod et al, 2005; van Eyk et al, 2011, 2012). Some of these diseases, however, have repeat expansions located within untranslated RNAs and/or arise from repeat sequences that cannot encode polyglutamine ( Figure 1 ; Richards, 2001; La Spada and Taylor, 2010).…”

Section: Is There a Common Pathogenic Agent?mentioning

confidence: 99%

“…(1) RNA sequestration – via alternative splicing (Mankodi et al, 2002; Ranum and Day, 2004) or Akt/GSK3β pathway (van Eyk et al, 2011; Jones et al, 2012; Lawlor et al, 2012). (2) RAN (repeat associated non-AUG) Translation (Zu et al, 2011; Ash et al, 2013; Mori et al, 2013; Todd et al, 2013).…”

Section: Mechanisms Of Rna-initiated Pathologymentioning

confidence: 99%

“…In muscle cells, RNAs from expanded alleles of either repeat are able to bind and sequester alternative splicing factors (muscleblind and CUG-BP) and in so doing, perturb the splicing pathways of proteins for which alternative splicing is a necessary step for their complete range of functions (Mankodi et al, 2002; Ranum and Day, 2004). It is now generally accepted that RNA is the common pathogenic agent in these diseases most likely through its impact on alternative splicing, although this has recently been challenged with evidence that GSK3β mediates at least some aspects of the RNA-based pathology in myotonic dystrophy (Jones et al, 2012) and in a Drosophila model (van Eyk et al, 2011). …”

Section: Mechanisms Of Rna-initiated Pathologymentioning

confidence: 99%

“…Drosophila models of expanded repeat diseases have been described that specifically investigate the intrinsic toxicity of both translated and untranslated expanded repeat sequences (Lawlor et al, 2011; van Eyk et al, 2011, 2012; Samaraweera et al, 2013). In one study (Lawlor et al, 2011), a single line of Drosophila expressing untranslated CAG was identified with a marked degenerative phenotype (whereas multiple other random insertion lines of the same transgene had no such phenotype).…”

Section: Mechanisms Of Rna-initiated Pathologymentioning

confidence: 99%

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RNA pathogenesis via Toll-like receptor-activated inflammation in expanded repeat neurodegenerative diseases

Richards¹,

Samaraweera²,

Eyk³

et al. 2013

Front. Mol. Neurosci.

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Previously, we hypothesized that an RNA-based pathogenic pathway has a causal role in the dominantly inherited unstable expanded repeat neurodegenerative diseases. In support of this hypothesis we, and others, have characterized rCAG.rCUG100 repeat double-strand RNA (dsRNA) as a previously unidentified agent capable of causing pathogenesis in a Drosophila model of neurodegenerative disease. Dicer, Toll, and autophagy pathways have distinct roles in this Drosophila dsRNA pathology. Dicer dependence is accompanied by cleavage of rCAG.rCUG100 repeat dsRNA down to r(CAG)7 21-mers. Among the “molecular hallmarks” of this pathway that have been identified in Drosophila, some [i.e., r(CAG)7 and elevated tumor necrosis factor] correlate with observations in affected people (e.g., Huntington’s disease and amyotrophic lateral sclerosis) or in related animal models (i.e., autophagy). The Toll pathway is activated in the presence of repeat-containing dsRNA and toxicity is also dependent on this pathway. How might the endogenously expressed dsRNA mediate Toll-dependent toxicity in neuronal cells? Endogenous RNAs are normally shielded from Toll pathway activation as part of the mechanism to distinguish “self” from “non-self” RNAs. This typically involves post-transcriptional modification of the RNA. Therefore, it is likely that rCAG.rCUG100 repeat dsRNA has a characteristic property that interferes with or evades this normal mechanism of shielding. We predict that repeat expansion leads to an alteration in RNA structure and/or form that perturbs RNA modification, causing the unshielded repeat RNA (in the form of its Dicer-cleaved products) to be recognized by Toll-like receptors (TLRs), with consequent activation of the Toll pathway leading to loss of cell function and then ultimately cell death. We hypothesize that the proximal cause of expanded repeat neurodegenerative diseases is the TLR recognition (and resultant innate inflammatory response) of repeat RNA as “non-self” due to their paucity of “self” modification.

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Mechanisms of RNA ‐Induced Toxicity in Diseases Characterised by CAG Repeat Expansions

Schilling

Griesche

Krauß

2016

Encyclopedia of Life Sciences

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Expansion disorders involving the trinucleotide CAG (cytosine–adenine–guanine) cause diverse progressive neurodegenerative phenotypes. The expanded CAG repeat can be located in the coding region, where it is translated into extended polyglutamine stretches or in the untranslated region (UTR) of the respective gene. The polyglutamine diseases are characterised by aggregate formation of polyglutamine protein, a process that is widely believed to play a role in disease development. In addition, there is emerging evidence showing that RNA (ribonucleic acid)‐mediated mechanisms also contribute to neurotoxicity in both polyglutamine diseases and diseases caused by elongated CAG repeat motifs in the UTR. Structurally, RNA with an expanded CAG repeat differs from normal RNA with a physiological CAG repeat stretch: expanded CAG repeat RNAs (CAG ex RNAs) fold into hairpin structures that increase in size and stability with increasing CAG repeat numbers. This article discusses how RNA molecules with expanded CAG repeats can execute abnormal functions that contribute to disease development. Key Concepts Several neurodegenerative diseases are caused by CAG trinucleotide repeat expansions. Pathologically expanded CAG repeat mRNAs fold into hairpin structures, which bind to and sequester diverse proteins. RNA‐mediated mechanisms contribute to neurotoxicity. RNA‐mediated neurotoxic functions depend on the subcellular localisation of the RNA, including cytosolic, nuclear and nucleolar mechanisms. Targeting pathologically expanded CAG repeat mRNAs represents a promising therapeutic approach for treating CAG trinucleotide repeat expansion disorders.

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Perturbation of the Akt/Gsk3-β signalling pathway is common to Drosophila expressing expanded untranslated CAG, CUG and AUUCU repeat RNAs

Cited by 29 publications

References 64 publications

GSK3β mediates muscle pathology in myotonic dystrophy

GSK3β mediates muscle pathology in myotonic dystrophy

RNA pathogenesis via Toll-like receptor-activated inflammation in expanded repeat neurodegenerative diseases

Mechanisms of RNA ‐Induced Toxicity in Diseases Characterised by CAG Repeat Expansions

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