Arocena Dolores Garcia, Iwahashi Christine K, Won Nelly, Beilina Alexandra, Ludwig Anna L, Tassone Flora, Schwartz Philip H, Hagerman Paul J
Department of Biochemistry and Molecular Medicine, University of California Davis, School of Medicine, Davis, CA 95616, USA.
Hum Mol Genet. 2005 Dec 1;14(23):3661-71. doi: 10.1093/hmg/ddi394. Epub 2005 Oct 20.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that affects some adult carriers of pre-mutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. FXTAS is thought to be caused by a toxic 'gain-of-function' of the expanded CGG-repeat FMR1 mRNA, which is found in the neuronal and astrocytic intranuclear inclusions associated with the disorder. Using a reporter construct with a FMR1 5' untranslated region harboring an expanded (premutation) CGG repeat, we have demonstrated that intranuclear inclusions can be formed in both primary neural progenitor cells and established neural cell lines. As with the inclusions found in post-mortem tissue, the inclusions induced by the expanded CGG repeat are alphaB-crystallin-positive; however, inclusions in culture are not associated with ubiquitin, indicating that incorporation of ubiquitinated proteins is a later event in the disease process. The absence of ubiquitinated proteins also argues against a model in which inclusion formation is due to a failure of the proteasomal degradative machinery. The presence of the expanded CGG repeat, as RNA, results in reduced cell viability as well as the disruption of the normal architecture of lamin A/C within the nucleus. This last observation, and the findings that lamin A/C is present in both the inclusions of FXTAS patients and the inclusions in cell culture, suggests that lamin A/C dysregulation may be a component of the pathogenesis of FXTAS; in particular, the Charcot-Marie-Tooth-type neuropathy associated with FXTAS may represent a functional laminopathy.
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，影响脆性X智力低下1（FMR1）基因前突变等位基因（55 - 200个CGG重复序列）的一些成年携带者。FXTAS被认为是由扩增的CGG重复FMR1 mRNA的毒性“功能获得”引起的，这种mRNA存在于与该疾病相关的神经元和星形细胞核内包涵体中。使用带有含有扩增（前突变）CGG重复序列的FMR1 5'非翻译区的报告构建体，我们已经证明在原代神经祖细胞和已建立的神经细胞系中都可以形成核内包涵体。与在尸检组织中发现的包涵体一样，由扩增的CGG重复序列诱导的包涵体是αB - 晶状体蛋白阳性的；然而，培养物中的包涵体与泛素无关，这表明泛素化蛋白的掺入是疾病过程中的后期事件。泛素化蛋白的缺失也与一种模型相悖，该模型认为包涵体形成是由于蛋白酶体降解机制的失败。作为RNA的扩增CGG重复序列的存在导致细胞活力降低以及核内lamin A/C正常结构的破坏。最后这一观察结果，以及lamin A/C存在于FXTAS患者的包涵体和细胞培养物中的包涵体中的发现，表明lamin A/C失调可能是FXTAS发病机制的一个组成部分；特别是，与FXTAS相关的夏科 - 马里 - 图斯型神经病变可能代表一种功能性核纤层蛋白病。
