【摘 要】
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Studies on myotonic dystrophy type 1(DM1)have led to the RNA-mediated disease model for hereditary disorders caused by noncoding microsatellite expansions.This model proposes that DM1 disease manifest
【机 构】
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Department of Neurology,Navy General Hospital of PLA,Beijing 100048,China
【出 处】
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第九届海内外华人神经科学家研讨会(The 9th Symposium for Chinese Neuroscientis
论文部分内容阅读
Studies on myotonic dystrophy type 1(DM1)have led to the RNA-mediated disease model for hereditary disorders caused by noncoding microsatellite expansions.This model proposes that DM1 disease manifestations are caused by a reversion to fetal RNA processing patterns in adult tissues due to the expression of toxic CUG RNA expansions(CUGexp)leading to decreased MBNL,but increased CELF,alternative splicing activities.Here,we test this model in vivo using the mouse HSALR poly(CUG)model for DM1 and recombinant adeno-associated virus(rAAV)-mediated transduction of specific splicing factors.Surprisingly,systemic overexpression of HNRNPA1,not previously linked to DM1,also shifted DM1-relevant splicing targets to fetal isoforms resulting in decreased lifespan with severe muscle weakness/myopathy as early as 4-6 weeks post-transduction whereas rAAV controls were unaffected.Minigene reporter analysis demonstrated that HNRNPA1 regulates DM1-relevant splicing targets and HITS-CLIP of rAAV-mycHnrnpa1 injected muscle reveals direct interactions of HNRNPA1 with these targets in vivo.Similar to CELF1,HNRNPA1 protein levels decrease during postnatal development but are elevated in both regenerating mouse muscle and DM1 skeletal muscle.Our studies suggest that CUGexp RNA triggers abnormal expression of multiple nuclear RNA binding proteins,including CELF1 and HNRNPA1,that antagonize MBNL activity to promote fetal splicing patterns.
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