In vivo magnetic resonance spectroscopy in the brain of Cdkl5 null mice reveals a metabolic profile indicative of mitochondrial dysfunctions
In vivo magnetic resonance spectroscopy in the brain of Cdkl5 null mice reveals a metabolic profile indicative of mitochondrial dysfunctions
复制标题
DOI：
10.1111/jnc.15300
复制
发表时间：
2021-02-02
影响因子：
4.7
通讯作者：
Frasca, Angelisa
中科院分区：
文献类型：
--
作者：
Carli, Sara;Chaabane, Linda;Frasca, Angelisa
X连锁CDKL5基因突变会导致CDKL5缺乏症（CDD），这是一种严重的神经发育疾病，主要特征是婴儿癫痫性脑病、智力障碍和自闭症特征。临床症状背后的分子机制在很大程度上仍然未知，在动物模型中鉴定可靠的生物标志物肯定有助于提高我们对 CDD 的理解以及评估治疗策略的功效。在这里，我们使用不同的磁共振 (MR) 方法来揭示成年小鼠大脑中 Cdkl5 缺陷的结构、功能或代谢特征。我们发现 Cdkl5 的缺失不会导致脑萎缩，但会影响不同的大脑区域，特别是海马体。通过体内质子磁共振波谱 (MRS)，我们在 Cdkl5 缺失大脑中发现了表明线粒体功能障碍的代谢失调。因此，我们发现 ATP 水平显着降低，线粒体电子传递链复合物 IV 的表达减少。相反，线粒体的数量似乎得到了保留。重要的是，我们报道了细胞能量平衡的主要调节因子之一——单磷酸腺苷激活蛋白激酶（AMPK）的激活存在显着缺陷，这可能会导致观察到的代谢损伤，并成为未来临床前试验的一个有趣的治疗靶点。总之，MRS 揭示了 Cdkl5 缺失大脑中存在代谢失调，提示线粒体功能障碍，这有助于促进我们对 Cdkl5 缺陷的理解，并使我们对以线粒体为目标作为 CDD 的治疗策略产生兴趣。
Mutations in the X-linked CDKL5 gene cause CDKL5 deficiency disorder (CDD), a severe neurodevelopmental condition mainly characterized by infantile epileptic encephalopathy, intellectual disability, and autistic features. The molecular mechanisms underlying the clinical symptoms remain largely unknown and the identification of reliable biomarkers in animal models will certainly contribute to increase our comprehension of CDD as well as to assess the efficacy of therapeutic strategies. Here, we used different Magnetic Resonance (MR) methods to disclose structural, functional, or metabolic signatures of Cdkl5 deficiency in the brain of adult mice. We found that loss of Cdkl5 does not cause cerebral atrophy but affects distinct brain areas, particularly the hippocampus. By in vivo proton-MR spectroscopy (MRS), we revealed in the Cdkl5 null brain a metabolic dysregulation indicative of mitochondrial dysfunctions. Accordingly, we unveiled a significant reduction in ATP levels and a decrease in the expression of complex IV of mitochondrial electron transport chain. Conversely, the number of mitochondria appeared preserved. Importantly, we reported a significant defect in the activation of one of the major regulators of cellular energy balance, the adenosine monophosphate-activated protein kinase (AMPK), that might contribute to the observed metabolic impairment and become an interesting therapeutic target for future preclinical trials. In conclusion, MRS revealed in the Cdkl5 null brain the presence of a metabolic dysregulation suggestive of a mitochondrial dysfunction that permitted to foster our comprehension of Cdkl5 deficiency and brought our interest towards targeting mitochondria as therapeutic strategy for CDD.