Contributors to FXTAS Progression

总结 FMR 1前突变的携带者在该基因的5' UTR处具有扩展的CGG重复。 携带者患脆性X相关震颤/共济失调综合征（FXTAS）的风险更高， 一种进行性神经变性疾病，伴有震颤和共济失调以及缺陷 认知、学习和其他神经心理学问题（抑郁、焦虑）。 FXTAS中的神经退行性变伴随着氧化应激增加， 线粒体生物能量能力，有限的未折叠蛋白质反应和较差的 以神经炎症过程为特征。令人惊讶的是，并不是所有的前突变携带者 发展FXTAS，从较温和到更有害阶段的进展是高度可变的 即使在年龄相当的受试者中。到目前为止，FXTAS还没有治愈方法或预防其 发展外泌体被认为是介导多种疾病中的病理生理信号传导。 靶细胞及其浓度在与炎症相关的疾病中激增。这里我们 假设带有有害物质的循环外泌体是发病的原因， 和/或疾病的进展。为此，我们将从血浆中表征外泌体， 从性别和年龄匹配的非携带者、携带和不携带FXTAS的携带者获得。的 彻底的表征将需要评估数量和大小、miRNA和蛋白质 侧写定性将作为一个平台，以确定定性和定量 差异以及确定不同生物途径的参与。推定的 将通过以下方法评估来源于具有和不具有FXTAS的载体的外泌体的“毒性”作用： 评估靶细胞（神经元和神经胶质）的生物能量学。这些研究将提供一个 了解外泌体成分对发病的影响的机制 线粒体功能障碍（如在FXTAS携带者中观察到的）和 共济失调和震颤，FXTAS受影响受试者的关键特征。

SUMMARY Carriers of the FMR1 premutation have expanded CGG repeats at the 5’ UTR of this gene. Carriers have a higher risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a progressive neurodegenerative disease accompanied by tremor and ataxia as well as deficits in cognition, learning, and other neuropsychological issues (depression, anxiety). Neurodegeneration in FXTAS is accompanied by increased oxidative stress, lower mitochondrial bioenergetic capacity, limited unfolded protein response and a poorly characterized neuroinflammatory process. Surprisingly, not all carriers of the premutation develop FXTAS and the progression from milder to more detrimental stages is highly variable even in subjects with comparable age. As of today, there is no cure for FXTAS or to prevent its development. Exosomes are proposed to mediate pathophysiological signaling in a variety of target cells and their concentration spike in diseases associated with inflammation. Here, we hypothesize that circulating exosomes with detrimental cargoes are contributors to the onset and/or the progression of the disease. To this end, we will characterize exosomes from plasma obtained from sex- and age-matched noncarriers, carriers with and without FXTAS. The thorough characterization will entail evaluation of number and size, miRNA, and protein profiling. The characterization will serve as a platform to identify qualitative and quantitative differences as well as to identify the involvement of different biological pathways. The putative “toxic” effect of exosomes derived from carriers with and without FXTAS will be assessed by evaluating the bioenergetics of target cells (neurons and glia). These studies will provide an insight on the mechanism underlying the impact of exosomal components to the onset of mitochondrial dysfunction (as it is observed in carriers with FXTAS) and the progression of ataxia and tremors, key features of FXTAS-affected subjects.