Microcephaly refers to a neurodevelopmental condition with smaller than expected head size and affects approximately 1 in 1,000 new born babies in the United States. Severe progressive microcephaly is also accompanied with neurodegeneration and seizures. Recent studies reveal that recessive mutations in aminoacyl-tRNA synthetases, a group of essential enzymes required for protein synthesis, cause progressive microcephaly. How such mutations lead to cellular toxicity and disorder of the central nervous system remains to be defined. Our previous work has identified disease-causing mutations in glutaminyl- (QARS) and alanyl- (AARS) tRNA synthetases in microcephaly patients, and suggests that such mutations lead to both decreased aminoacylation efficiency and protein misfolding. We have also identified a novel candidate gene causing progressive microcephaly, which tryptophanyl- (WARS) tRNA synthetases. In the proposed work, we will generate patient-derived lymphoblastoid and induced pluripotent stem cell lines, as well as yeast and neuronal cell lines carrying pathogenic mutations. The resulting cells will be used to determine: (1) the impact of QARS mutations on protein synthesis and cellular toxicity; (2) the impact of aminoacylation and editing defects in AARS; and (3) the effects of mutations in WARS and seryl-tRNA synthetase associated with microcephaly on aminoacylation and protein misfolding. This work will reveal the cellular toxicity of defective protein synthesis and provide insights into the genetic causes of microcephaly. The various cell lines developed in this study will also be valuable for future studies of protein synthesis defects and the mechanism of protein synthesis quality control.
Progressive microcephaly is a severe form of neurological disorder with largely uncharacterized pathogenic mechanisms. Studying the cellular and structural impact of disease-causing mutations in aminoacyl-tRNA synthetases is expected to reveal the underlying mechanisms leading to progressive microcephaly and provide basis for future therapeutic interventions.
