Modelling the Role of Mitochondrial Aspartyl-tRNA Synthetase (DARS2) in Neurodegeneration - Inhibition of CLPP protease as a potential therapeutic intervention

在过去的20年里，人们对导致线粒体疾病的遗传和生化机制的了解呈指数级增长，线粒体疾病通常被描述为中枢神经系统常见的临床异质性受累的脑肌病，包括最近增加的白质脑病(特别是LBSL-脑干和脊髓受累的白质脑病和高脑乳酸)。不幸的是，这并没有导致有效的治疗方法的发展，在任何程度上都可以改善这些疾病的临床过程和结果。治疗的主要目的是缓解症状，减缓疾病的进展，或者仅限于姑息治疗。患者最常接受的治疗是维生素、辅酶和营养补充剂的鸡尾酒，这些似乎对大多数线粒体疾病没有显著影响。我们相信，我们到目前为止开发的小鼠模型以及我们计划在未来建立的模型将使我们能够探索线粒体疾病治疗方法的新途径。我们最近发现，CLPP通过耗尽线粒体基质蛋白水解酶来减缓线粒体翻译的速度，可以改善由于天冬氨酰-tRNA合成酶(DARS2)缺失而引起的线粒体心肌病。我们的初步数据表明，同样的干预措施可能在前脑和海马神经元特异性Dars2基因敲除小鼠(Dars2NEKO)中保守，似乎概括了LBSL的特征，LBSL是一种通常由人类DARS2突变引起的疾病。这些结果还将在其他神经元群体和在原代神经元培养中探索的分子机制上进行测试。因此，我们的初步结果为进一步探索CLPP缺乏症的治疗可能性开辟了令人兴奋的可能性，无论是由于基因操作还是使用特定的抑制剂，我们希望在这个项目中进行探索。

The last 20 years have witnessed an exponential increase in understanding the genetic and biochemical mechanisms leading to mitochondrial diseases, often described as encephalomyopathies with common and clinically heterogeneous involvement of central nervous system, including recently added leukoencephalopathies (LBSL - leukoencephalopathy with brain stem and spinal cord involvement and high brain lactate, in particular). Unfortunately, this has not resulted in the development of effective therapeutic approaches, amenable of improving the clinical course and outcome of these conditions to any significant extent. Therapies are mainly aimed at alleviating symptoms, slow down the disease’s progression or limited to only palliative care. Patients are most often treated with cocktails of vitamins, cofactors and nutritional supplements that seem not to have a significant impact on most mitochondrial diseases. We believe that mouse models that we have developed to date and the ones we propose to generate in the future will allow us to explore novel paths for therapeutic approaches of mitochondrial diseases. We have recently shown that slowing down the rate of mitochondrial translation by depleting mitochondrial matrix protease, CLPP could ameliorate mitochondrial cardiomyopathy caused by the loss of aspartyl-tRNA synthetase (DARS2). Our preliminary data suggest that the same intervention might have conserved in the forebrain and hippocampal neuron-specific Dars2 knockout mice (Dars2NEKO) that seems to recapitulate features of LBSL, a disease commonly caused by DARS2 mutations in humans. These results will also be tested on other neuronal populations and molecular mechanisms explored in primary neuronal cultures. Therefore, our preliminary results open an exciting possibility to further explore the therapeutic possibilities of CLPP deficiency induced either by genetic manipulation or usage of specific inhibitors that we would like to pursue in this project.