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

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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.