Aradjanski Marijana, Dogan Sukru Anil, Lotter Stephan, Wang Shuaiyu, Hermans Steffen, Wibom Rolf, Rugarli Elena, Trifunovic Aleksandra
Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
Hum Mol Genet. 2017 Nov 1;26(21):4181-4189. doi: 10.1093/hmg/ddx307.
Although mitochondria are ubiquitous, each mitochondrial disease has surprisingly distinctly different pattern of tissue and organ involvement. Congruently, mutations in genes encoding for different mitochondrial tRNA synthetases result in the development of a very flamboyant group of diseases. Mutations in some of these genes, including aspartyl-tRNA synthetase (DARS2), lead to the onset of a white matter disease-leukoencephalopathy with brainstem and spinal cord involvement, and lactate elevation (LBSL) characterized by progressive spastic ataxia and characteristic leukoencephalopathy signature with multiple long-tract involvements. Puzzled by the white matter disease phenotypes caused by DARS2 deficiency when numerous other mutations in the genes encoding proteins involved in mitochondrial translation have a detrimental effect predominantly on neurons, we generated transgenic mice in which DARS2 was specifically depleted in forebrain-hippocampal neurons or myelin-producing cells. Our results now provide the first evidence that loss of DARS2 in adult neurons leads to strong mitochondrial dysfunction and progressive loss of cells. In contrast, myelin-producing cells seem to be resistant to cell death induced by DARS2 depletion despite robust respiratory chain deficiency arguing that LBSL might originate from the primary neuronal and axonal defect. Remarkably, our results also suggest a role for early neuroinflammation in the disease progression, highlighting the possibility for therapeutic interventions of this process.
尽管线粒体普遍存在，但每种线粒体疾病在组织和器官受累模式上却有着惊人的明显差异。同样，编码不同线粒体tRNA合成酶的基因突变会导致一系列非常复杂的疾病。这些基因中的一些突变，包括天冬氨酰-tRNA合成酶（DARS2），会引发一种白质疾病——伴有脑干和脊髓受累以及乳酸升高的白质脑病（LBSL），其特征为进行性痉挛性共济失调以及伴有多处长束受累的特征性白质脑病表现。当线粒体翻译相关蛋白质编码基因中的众多其他突变主要对神经元产生有害影响时，DARS2缺乏所导致的白质疾病表型令人困惑，我们因此构建了转基因小鼠，其中DARS2在前脑海马神经元或产生髓磷脂的细胞中被特异性敲除。我们的研究结果首次证明，成年神经元中DARS2的缺失会导致严重的线粒体功能障碍和细胞的渐进性丧失。相比之下，尽管存在严重的呼吸链缺陷，但产生髓磷脂的细胞似乎对DARS2缺失诱导的细胞死亡具有抗性，这表明LBSL可能起源于原发性神经元和轴突缺陷。值得注意的是，我们的研究结果还表明早期神经炎症在疾病进展中发挥作用，突出了针对这一过程进行治疗干预的可能性。
