Sellier Chantal, Buijsen Ronald A M, He Fang, Natla Sam, Jung Laura, Tropel Philippe, Gaucherot Angeline, Jacobs Hugues, Meziane Hamid, Vincent Alexandre, Champy Marie-France, Sorg Tania, Pavlovic Guillaume, Wattenhofer-Donze Marie, Birling Marie-Christine, Oulad-Abdelghani Mustapha, Eberling Pascal, Ruffenach Frank, Joint Mathilde, Anheim Mathieu, Martinez-Cerdeno Veronica, Tassone Flora, Willemsen Rob, Hukema Renate K, Viville Stéphane, Martinat Cecile, Todd Peter K, Charlet-Berguerand Nicolas
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, University of Strasbourg, 67400 Illkirch, France.
Department of Clinical Genetics, Erasmus MC, 3015 Rotterdam, the Netherlands.
Neuron. 2017 Jan 18;93(2):331-347. doi: 10.1016/j.neuron.2016.12.016. Epub 2017 Jan 5.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a limited expansion of CGG repeats in the 5' UTR of FMR1. Two mechanisms are proposed to cause FXTAS: RNA gain-of-function, where CGG RNA sequesters specific proteins, and translation of CGG repeats into a polyglycine-containing protein, FMRpolyG. Here we developed transgenic mice expressing CGG repeat RNA with or without FMRpolyG. Expression of FMRpolyG is pathogenic, while the sole expression of CGG RNA is not. FMRpolyG interacts with the nuclear lamina protein LAP2β and disorganizes the nuclear lamina architecture in neurons differentiated from FXTAS iPS cells. Finally, expression of LAP2β rescues neuronal death induced by FMRpolyG. Overall, these results suggest that translation of expanded CGG repeats into FMRpolyG alters nuclear lamina architecture and drives pathogenesis in FXTAS.
脆性X相关震颤/共济失调综合征（FXTAS）是一种神经退行性疾病，由FMR1基因5'非翻译区的CGG重复序列有限扩增引起。目前提出了两种导致FXTAS的机制：RNA功能获得，即CGG RNA隔离特定蛋白质；以及将CGG重复序列翻译成含多聚甘氨酸的蛋白质FMRpolyG。在这里，我们构建了表达有或没有FMRpolyG的CGG重复RNA的转基因小鼠。FMRpolyG的表达具有致病性，而单独的CGG RNA表达则不具有致病性。FMRpolyG与核纤层蛋白LAP2β相互作用，并破坏来自FXTAS诱导多能干细胞分化的神经元中的核纤层结构。最后，LAP2β的表达挽救了由FMRpolyG诱导的神经元死亡。总体而言，这些结果表明，扩展的CGG重复序列翻译成FMRpolyG会改变核纤层结构，并驱动FXTAS的发病机制。
