tRNA-sequestration as an underlying molecular mechanism of tyrosyl-tRNA synthetase-associated DI-CMTC pathology

氨基酰基trna合成酶（aaRS）是蛋白质翻译的关键；它们用同源氨基酸对trna进行氨基酰化。六种不同的AARSs的杂合突变与破坏性的显性遗传性charco - marie - tooth （CMT）周围神经病变有关，其特征是周围运动和感觉轴突变性，导致进行性肌肉无力、萎缩和感觉功能障碍。不同CMT形式的潜在分子机制及其组织特异性作用仍然知之甚少。我们最近报道了CMT2D病理与glyyl - trna合成酶（GARS）突变相关的新机制，GARS是一类aaRS。GARS的cmt突变形式紧密结合同源trna而不能释放它们，因此，用于翻译的glyyl - trnagly耗尽，从而导致核糖体在Gly密码子处停滞。YARS的杂合突变是导致DI-CMTC病理的原因。通过分析果蝇和小鼠CMT模型（YarsE196K小鼠）中CMT突变tyroyl -tRNA合成酶（YARS）变异体的tRNA结合和释放动力学，结合全细胞翻译速度和表达分析，我们将确定另一类与CMT病理相关的aaRS的分子机制。我们期望这种多层次的方法将揭示与CMT病理有因果关系的I类和II类aars突变的共同和独特的机制方面。

Aminoacyl-tRNA-synthetases (aaRS) are pivotal for protein translation; they aminoacylate tRNAs with cognate amino acid. Heterozygous mutations in six distinct AARSs are connected to devastating dominantly inherited Charcot-Marie-Tooth (CMT) peripheral neuropathies, which is characterized by degeneration of peripheral motor and sensory axons, leading to progressive muscle weakness and wasting and sensory dysfunction. The underlying molecular mechanisms of different CMT forms and their tissue-specific effect remain poorly understood. We recently reported a novel mechanism underlying the CMT2D pathology linked to mutations in the glycyl-tRNA synthetase (GARS), a class II aaRS. The CMT-mutant forms of GARS tightly bind the cognate tRNAs and fail to release them, thus, depleting glycyl-tRNAGly for translation and consequently causing ribosome stalling at Gly codons. Heterozygous mutations in YARS are causal to DI-CMTC pathology. By analysing the kinetics of tRNA binding and release of CMT-mutant tyrosyl-tRNA-synthetase (YARS) variants in Drosophila and mouse CMT models (YarsE196K mice), combined with cell-wide analysis of translation speed and expression, we will determine the molecular mechanism of another class I aaRS associated with CMT pathologies. We expect that this multilayered approach will reveal insights into common and distinct mechanistic facets of mutations in class I and class II aaRSs with a causal link to CMT pathologies.