In vivo magnetic resonance spectroscopy in the brain of Cdkl5 null mice reveals a metabolic profile indicative of mitochondrial dysfunctions

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.
DOI: 10.1111/jnc.15300

X连锁CDKL5基因（X-linked CDKL5 gene）的突变会引发CDKL5缺乏症（CDKL5 deficiency disorder, CDD），这是一种严重的神经发育疾病，主要以婴儿性癫痫性脑病、智力障碍及自闭症特征为核心临床表现。目前该疾病临床症状背后的分子机制仍未完全阐明，而在动物模型中鉴定可靠的生物标志物，无疑将有助于加深我们对CDD的认知，并为治疗策略的疗效评估提供关键支持。
本研究采用多种磁共振（Magnetic Resonance, MR）技术，解析成年小鼠脑部Cdkl5缺乏的结构、功能及代谢特征。研究发现，Cdkl5缺失并不会导致大脑萎缩，但会对特定脑区造成影响，其中尤以海马体最为显著。通过活体质子磁共振波谱（proton-MR spectroscopy, MRS），我们在Cdkl5敲除小鼠的脑部检测到提示线粒体功能异常的代谢紊乱。进一步实验显示，三磷酸腺苷（ATP）水平显著降低，同时线粒体电子传递链复合物IV的表达量出现下调；与之相反，线粒体的数量并未发生明显变化。尤为重要的是，我们发现细胞能量平衡的核心调控因子之一——腺苷酸活化蛋白激酶（adenosine monophosphate-activated protein kinase, AMPK）的激活存在显著缺陷，这可能是导致上述代谢损伤的关键诱因，也有望成为未来临床前试验的潜在治疗靶点。
综上，磁共振波谱分析在Cdkl5敲除小鼠脑部发现了提示线粒体功能异常的代谢紊乱，这一发现加深了我们对Cdkl5缺乏症的理解，并将研究方向指向以线粒体作为CDD治疗策略的靶点。
DOI: 10.1111/jnc.15300