Retrotransposon activation contributes to fragile X premutation rCGG-mediated neurodegeneration

Division of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China.
Human Molecular Genetics (Impact Factor: 6.39). 09/2011; 21(1):57-65. DOI: 10.1093/hmg/ddr437
Source: PubMed


Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder associated with fragile X premutation
carriers. Previous studies have shown that fragile X rCGG repeats are sufficient to cause neurodegeneration and that the rCGG-repeat-binding
proteins Pur α and heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 could modulate rCGG-mediated neuronal toxicity. Mobile
genetic elements or their remnants populate the genomes, and the activities of these elements are tightly controlled for the
fitness of host genomes in different organisms. Here we provide both biochemical and genetic evidence to show that the activation
of a specific retrotransposon, gypsy, can modulate rCGG-mediated neurodegeneration in an FXTAS Drosophila model. We find that one of the rCGG-repeat-binding proteins, hnRNP A2/B1, is involved in this process via interaction with
heterochromatin protein 1. Knockdown of gypsy RNA by RNAi could suppress the neuronal toxicity caused by rCGG repeats. These data together point to a surprisingly active
role for retrotransposition in neurodegeneration.

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    • "In higher eukaryotes, hnRNPA1 is important in telomere regulation (LaBranch et al. 1998; Ford et al. 2002; Zhang et al. 2006; Flynn et al. 2011; Le et al. 2013). Drosophila hnRNPA1 homolog, Hrb87F/Hrp36, co-localizes and physically associates with HP1 on polytene chromosomes (Piacentini et al. 2009; Tan et al. 2012). Hrb87F is known to have roles in gene expression, omega speckle dynamics, splicing, neurodegeneration, organization of nuclear matrix and heterochromatin formation (Piacentini et al. 2009; Mallik and Lakhotia 2010; Singh and Lakhotia 2012, 2015; Picollo et al. 2014). "
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    DESCRIPTION: Abstract Unlike the telomerase dependent mammalian telomeres, HeT-A, TART and TAHRE (HTT) retroposon arrays regulate Drosophila telomere length. Cap prevents telomeric associations (TA) and telomeric fusions (TF). Our results suggest important roles of Hrb87F in telomeric HTT array and cap maintenance in Drosophila. All chromosome arms, except 2L, in Df(3R)Hrb87F homozygotes (Hrb87F-null) displayed significantly elongated telomeres with amplified HTT arrays and high TA, all of which resolved without damage. Presence of FLAG-Hrb87F on cap and sub-telomeric regions following hsFLAG-Hrb87F transgene expression in Df(3R)Hrb87F homozygotes suppressed TA without affecting telomere length. A normal X-chromosome telomere expanded within five generations in Hrb87F-null background and displayed high TA, but not when hsFLAG-Hrb87F was co-expressed. Tel1/Gaiano line or HP1 loss of function mutant derived expanded telomeres carry Hrb87F on cap and HTT arrays while Hrb87F-null telomeres have HP1 and HOAP on caps and expanded HTT arrays. ISWI, seen only on cap on normal telomeres, was abundant on Hrb87F-null expanded HTT arrays. Extended telomeres derived from Tel1 (Gaiano) or HP1-null mutation background interact with those from Hrb87F-null since the end association frequency was negligible in Df(3R)Hrb87F/+ nuclei but increased significantly in co-presence of Tel1 or HP1-null based expanded telomere/s. Together these suggest complex interactions between members of the proteome of telomere so that absence of any key member leads to telomere expansion and/or enhanced TA/TF. HTT expansion in Hrb87F-null condition is not developmental but a germline event presumably because absence of Hrb87F in germline may deregulate HTT retroposition/replication leading to telomere elongation.
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    • "Another RNA-binding protein that can interact directly with CGG repeats is hnRNP A2/B1, which in addition to splicing, plays a role as a trans -acting factor in neuronal RNA transport pathways (Sofola et al. , 2007a ; Muslimov et al. , 2011 ). This protein has recently also been suggested to recruit heterochromatin protein 1 (HP1) to inhibit the expression of specific transposons (Tan et al. , 2012 ). The hnRNP A2/B1 depletion by CGG sequestration results in insufficient recruitment of HP1 and increases the expression of transposons, promoting neurodegeneration. "
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    ABSTRACT: Abstract Tandem repeats of various trinucleotide motifs are frequent entities in transcripts, and RNA structures formed by these sequences depend on the motif type and number of reiterations. The functions performed by normal triplet repeats in transcripts are poorly understood, but abnormally expanded repeats of certain types trigger pathogenesis in several human genetic disorders known as the triplet repeat expansion diseases (TREDs). The diseases caused by expanded non-coding CUG and CGG repeats in transcripts include myotonic dystrophy type 1 and fragile X-associated tremor ataxia syndrome. Another group of disorders in which transcripts containing translated CAG repeats play an auxiliary role in pathogenesis include Huntington's disease and several spinocerebellar ataxias. In this review, we gathered existing knowledge regarding the structural features of triplet repeats in transcripts and discussed this in the context of various pathogenic mechanisms assigned to toxic RNA repeats. These mechanisms include aberrant alternative splicing, the inhibition of nuclear transport and export, induction of the innate immune response, alteration of a microRNA biogenesis pathway and abnormal activation of an RNA interference pathway. We also provide ideas for future investigations to reveal further mechanisms of pathogenesis directly triggered by mutant RNA repeats in TREDs.
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    • "On the other hand, there also is emerging evidence that unregulated activation of TEs is associated with neuropathology. TE activation in brain has been observed in macular degeneration [14], Rett syndrome [11], Prion diseases [13], [29], Fragile-X associated tremor/ataxia syndrome (FXTAS) [15] and ALS [12]. Moreover, for the cases of macular degeneration and FXTAS, there is evidence that activation of SINEs and an LTR-retrotransposon respectively may contribute to the observed pathology [14], [15]. "
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    ABSTRACT: Elevated expression of specific transposable elements (TEs) has been observed in several neurodegenerative disorders. TEs also can be active during normal neurogenesis. By mining a series of deep sequencing datasets of protein-RNA interactions and of gene expression profiles, we uncovered extensive binding of TE transcripts to TDP-43, an RNA-binding protein central to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Second, we find that association between TDP-43 and many of its TE targets is reduced in FTLD patients. Third, we discovered that a large fraction of the TEs to which TDP-43 binds become de-repressed in mouse TDP-43 disease models. We propose the hypothesis that TE mis-regulation contributes to TDP-43 related neurodegenerative diseases.
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