Nuclear Accumulation of Stress Response mRNAs Contributes to the Neurodegeneration Caused by Fragile X Premutation rCGG Repeats

Qurashi, Abrar; Li, Wendi; Zhang, Jianying; Peng, Junmin; Jin, Peng

doi:10.1371/journal.pgen.1002102

Cited by 62 publications

(64 citation statements)

References 41 publications

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“…Genetic analysis demonstrated that the RNA helicase RM62/ Lip and the actin-binding protein Hts function as modulators of rCGG repeat induced toxicity. 29 We also identified three of these proteins in our analysis GFP-Pur-α interactors in ovaries (Ypsilon Schachtel and Hsc4) or somatic S2-cells (dFmr1), despite the very different technical approaches and tissues (ovaries or cells vs. brain extract). A common conclusion of both studies is that Pur-α likely associates with mRNPs before their export from the nucleus, then travels together with the mRNP to the cytoplasm.…”

Section: Discussionmentioning

confidence: 81%

Drosophila Pur-α binds to trinucleotide-repeat containing cellular RNAs and translocates to the early oocyte

et al. 2012

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Section: Discussionmentioning

confidence: 81%

Drosophila Pur-α binds to trinucleotide-repeat containing cellular RNAs and translocates to the early oocyte

et al. 2012

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“…This observation suggests that accumulated RNA repeats might interfere with the proper delivery of mRNAs from nuclei to cytosol, eventually affecting gene expression. As a matter of fact, Fragile X premutated rCGG repeats, which are responsible for Fragile X-associate tremor/ataxia syndrome (FXTAS), induce nuclear accumulation of mRNAs, including mRNAs involved in stress response, in a Drosophila model (Qurashi et al, 2011). Notably, this process is mediated by the interaction of the Drosophila homologue of the p68 RNA helicase, Rm62, with Pura, whose localization is profoundly affected by C9orf72 expression, as shown in this work, and has been suggested to play a pivotal role in C9orf72-mediated neurodegeneration in Drosophila (Xu et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Nuclear accumulation of mRNAs underlies G4C2 repeat-induced translational repression in a cellular model of C9orf72 ALS

Rossi

Serrano

Gerbino

et al. 2015

Journal of Cell Science

108

129

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A common feature of non-coding repeat expansion disorders is the accumulation of RNA repeats as RNA foci in the nucleus and/or cytoplasm of affected cells. These RNA foci can be toxic because they sequester RNA-binding proteins, thus affecting various steps of post-transcriptional gene regulation. However, the precise step that is affected by C9orf72 GGGGCC (G4C2) repeat expansion, the major genetic cause of amyotrophic lateral sclerosis (ALS), is still poorly defined. In this work, we set out to characterise these mechanisms by identifying proteins that bind to C9orf72 RNA. Sequestration of some of these factors into RNA foci was observed when a (G4C2) 31 repeat was expressed in NSC34 and HeLa cells. Most notably, (G4C2) 31 repeats widely affected the distribution of Pur-alpha and its binding partner fragile X mental retardation protein 1 (FMRP, also known as FMR1), which accumulate in intra-cytosolic granules that are positive for stress granules markers. Accordingly, translational repression is induced. Interestingly, this effect is associated with a marked accumulation of poly(A) mRNAs in cell nuclei. Thus, defective trafficking of mRNA, as a consequence of impaired nuclear mRNA export, might affect translation efficiency and contribute to the pathogenesis of C9orf72 ALS.

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“…All these findings indicate an important role for retrotransposition in neurodegeneration [36]. The role of Purα in rCGG-mediated neurodegeneration was further investigated by Qurashi et al [37]. They identified more than 100 proteins that interact with Purα through a proteomic approach.…”

Section: Purα and Fragile X Tremor/ataxia Syndromementioning

confidence: 96%

The role of Purα in neuronal development, the relationship between Purα and epilepsy in the current researches

et al. 2017

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Abstract. As a ubiquitous protein in the body, Purα has been considered to possess multiple regulatory functions from DNA replication and transcription to RNA transport and translation. The recent studies have proved that Purα protein played a vital role in neuronal development with the solid and abundant evidence both in transgenic mice and human genetic DNA analysis. The Purα knocked out mice models have been successfully established in two independent research groups and their results demonstrated that lack of Purα alters postnatal brain development. Mice lacking of Purα display decreased neurogenesis and impaired neuronal development. In the mouse brain, the expression level of Purα seems to be regulated with brain development. It starts to express Purα after birth and quickly reach to highest level in the third week. The recent studies also have proved that some neurodegenerative disease also linked with Purα, such as Fragile X-associated tremor/ataxia syndrome. rCGG-mediated neuronal toxicity could be modulated by heterogeneous nuclear ribonucleoprotei n A2/B1 and Purα, which is rCGG-repeat-binding proteins. The 5q31.3 microdeletion syndrome is another disorders that is associated with the mutation of Purα gene, it has been demonstrated that all the symptoms such as the neurocognitive impairment, neurodevelopmental delay and learning disability are caused by the mutation of Purα gene. In this mini review, we will retrospectively review the current progress of Purα in neuronal development and try to figure out the connections between these observed phenomena and the biological function of Purα.

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Nuclear Accumulation of Stress Response mRNAs Contributes to the Neurodegeneration Caused by Fragile X Premutation rCGG Repeats

Cited by 62 publications

References 41 publications

Drosophila Pur-α binds to trinucleotide-repeat containing cellular RNAs and translocates to the early oocyte

Drosophila Pur-α binds to trinucleotide-repeat containing cellular RNAs and translocates to the early oocyte

Nuclear accumulation of mRNAs underlies G4C2 repeat-induced translational repression in a cellular model of C9orf72 ALS

The role of Purα in neuronal development, the relationship between Purα and epilepsy in the current researches

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