< Back to previous page

Publication

Unraveling the nuclear function of tyrosyl-tRNA synthetase associated with Charcot-Marie-Tooth disease

Book - Dissertation

Aminoacyl-tRNA synthetases (aaRS) catalyse the ligation of tRNAs with their cognate amino acid, the first step in protein translation, making them indispensable in every organism. Despite being ubiquitously expressed, dominant mutations in these enzymes cause a peripheral neuropathy. This incurable disease affects the longest motor and sensory neurons in the human body leading to a progressive impairment of motor abilities and sensation, ultimately causing loss of ambulation. Patients affected by dominant mutations in six different aaRSs have a similar clinical presentation, suggesting a shared disease mechanism. Yet, this pathomechanism still remains to be elucidated. At first it was postulated that loss of the aaRS’ enzymatic activity is pathogenic. However, recent work reveals that a toxic gain of function is likely contributing to the neuropathy. Outside their central role in protein translation, aaRSs have acquired multiple non-canonical functions, which often relate to cellular compartments where protein translation is generally not taking place. Interestingly, all aaRSs associated with a peripheral neuropathy localise to the nucleus, but the relationship between their nuclear presence and the peripheral neuropathy has not been explored thus far. This study focuses on the nuclear role of tyrosyl-tRNA synthetase (TyrRS). This aaRS causes a subtype of a peripheral neuropathy, named Dominant Intermediate Charcot-Marie-Tooth type C (DI-CMTC). Conformational changes in the mutant TyrRS protein result in aberrant binding to components of the nuclear transcription machinery, supporting a toxic gain-of-function. As a result, a specific set of genes is uniquely misexpressed. The transcriptional changes particularly involve genes related to mitochondria. Furthermore, cellular and Drosophila models of DI-CMTC show fragmentation of mitochondria. Excluding the mutant protein from the nucleus, both genetically and pharmacologically, prevents the disease phenotypes in the models for TyrRS-induced peripheral neuropathy. Taken together, our data reveal the nucleus as the site of lesion in TyrRS-induced peripheral neuropathy, opening opportunities to study this putatively shared pathomechanism in aaRS-induced neurodegeneration. Our work paves the way for further development of new therapeutic strategies to treat peripheral neuropathies.
Number of pages: 183
Publication year:2019
Keywords:Doctoral thesis
Accessibility:Closed