Loesch Danuta Z, Kemp Bruce E, Bui Minh Q, Fisher Paul R, Allan Claire Y, Sanislav Oana, Ngoei Kevin R W, Atkinson Anna, Tassone Flora, Annesley Sarah J, Storey Elsdon
School of Psychology and Public Health, La Trobe University, Bundoora, VA, Australia.
Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VA, Australia.
Front Psychiatry. 2021 Nov 22;12:747268. doi: 10.3389/fpsyt.2021.747268. eCollection 2021.
Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder affecting carriers of premutation alleles (PM) of the X-linked FMR1 gene, which contain CGG repeat expansions of 55-200 range in a non-coding region. This late-onset disorder is characterised by the presence of tremor/ataxia and cognitive decline, associated with the white matter lesions throughout the brain, especially involving the middle cerebellar peduncles. Nearly half of older male and ~ 20% of female PM carriers develop FXTAS. While there is evidence for mitochondrial dysfunction in neural and some peripheral tissues from FXTAS patients (though less obvious in the non-FXTAS PM carriers), the results from peripheral blood mononuclear cells (PBMC) are still controversial. Motor, cognitive, and neuropsychiatric impairments were correlated with measures of mitochondrial and non-mitochondrial respiratory activity, AMPK, and TORC1 cellular stress-sensing protein kinases, and CGG repeat size, in a sample of adult FXTAS male and female carriers. Moreover, the levels of these cellular measures, all derived from Epstein- Barr virus (EBV)- transformed and easily accessible blood lymphoblasts, were compared between the FXTAS ( = 23) and non-FXTAS ( = 30) subgroups, and with baseline data from 33 healthy non-carriers. A significant hyperactivity of cellular bioenergetics components as compared with the baseline data, more marked in the non-FXTAS PMs, was negatively correlated with repeat numbers at the lower end of the CGG-PM distribution. Significant associations of these components with motor impairment measures, including tremor-ataxia and parkinsonism, and neuropsychiatric changes, were prevalent in the FXTAS subgroup. Moreover, a striking elevation of AMPK activity, and a decrease in TORC1 levels, especially in the non-FXTAS carriers, were related to the size of CGG expansion. The bioenergetics changes in blood lymphoblasts are biomarkers of the clinical status of FMR1 carriers. The relationship between these changes and neurological involvement in the affected carriers suggests that brain bioenergetic alterations are reflected in this peripheral tissue. A possible neuroprotective role of stress sensing kinase, AMPK, in PM carriers, should be addressed in future longitudinal studies. A decreased level of TORC1-the mechanistic target of the rapamycin complex, suggests a possible future approach to therapy 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，影响X连锁FMR1基因前突变等位基因（PM）的携带者，该基因在非编码区含有55 - 200范围内的CGG重复扩增。这种迟发性疾病的特征是存在震颤/共济失调和认知能力下降，与全脑白质病变相关，尤其累及小脑中脚。近一半的老年男性和20%的女性PM携带者会发展为FXTAS。虽然有证据表明FXTAS患者的神经和一些外周组织存在线粒体功能障碍（尽管在非FXTAS PM携带者中不太明显），但外周血单个核细胞（PBMC）的结果仍存在争议。在成年FXTAS男性和女性携带者样本中，运动、认知和神经精神障碍与线粒体和非线粒体呼吸活性、AMPK以及TORC1细胞应激感应蛋白激酶的测量值以及CGG重复序列大小相关。此外，比较了FXTAS组（n = 23）和非FXTAS组（n = 30）以及33名健康非携带者的基线数据，这些细胞测量值均来自爱泼斯坦-巴尔病毒（EBV）转化且易于获取的血液淋巴细胞。与基线数据相比，细胞生物能量学成分显著亢进，在非FXTAS PMs中更为明显，与CGG - PM分布下限的重复序列数呈负相关。这些成分与运动障碍测量值（包括震颤 - 共济失调和帕金森症）以及神经精神变化之间的显著关联在FXTAS亚组中普遍存在。此外，AMPK活性显著升高，TORC1水平降低，尤其是在非FXTAS携带者中，与CGG扩增的大小有关。血液淋巴细胞中的生物能量学变化是FMR1携带者临床状态的生物标志物。这些变化与受影响携带者神经受累之间的关系表明，大脑生物能量学改变反映在这种外周组织中。应激感应激酶AMPK在PM携带者中可能具有的神经保护作用，应在未来的纵向研究中加以探讨。TORC1水平降低——雷帕霉素复合物的机制靶点，提示了未来FXTAS治疗的一种可能方法。
