Abstract
Hereditary spastic paraplegia (HSP) is a neurodegeneration disease, one of the reasons is caused by autosomal recessive missense mutation of the karyogene that encodes phenylalanyl-tRNA synthetase 2, mitochondrial (FARS2). However, the molecular mechanism underlying FARS2-mediated HSP progression is unknown. Mitochondrial phenylalanyl-tRNA synthetase gene (PheRS-m) is the Drosophila melanogaster homolog gene of human FARS2. This study constructed a Drosophila HSP missense mutation model and a PheRS-m knockout model. Some of the mutant fly phenotypes included developmental delay, shortened lifespan, wing-structure abnormalities and decreased mobility. RNA-sequencing results revealed a relationship between abnormal phenotypes and the hedgehog (Hh) pathway. A qRT-PCR assay was used to determine the key genes (ptc, hib, and slmb) of the Hh pathway that exhibited increased expression during different developmental stages. We demonstrated that Hh signaling transduction is negatively regulated during the developmental stages of PheRS-m mutants but positively regulated during adulthood. By inducing the agonist and inhibitor of Hh pathway in PheRS-m larvae, the developmental delay in mutants can be partly salvaged or postponed. Collectively, our findings indicate that Hh signaling negatively regulates the development of PheRS-m mutants, subsequently leading to developmental delay.
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Acknowledgements
We thank Fungene Biotech (http://www.fungene.tech) and Guangzhou Genedenovo Biotechnology Co., Ltd for help.
Funding
This study was supported by the Key Innovative Project in Shaanxi, Grant/Award Number: 2021ZDLSF02-02, 2022KXJ-123; National Natural Science Foundation of China, Grant/Award Number: 81671476, 82271893.
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L. Mo and R. Li contributed to the conceptualization, data curation, data collection, data validation structural analysis, investigation, statistical analysis, visualization, and writing of the original draft. C. He contributed to the methodology, manuscript writing. Q. Chen and C. Xu contributed to data collection and statistical analysis. L. Shen, K. Chen and Y. Wu contributed to the conceptualization, project administration, and writing (editing). All authors contributed to the article and approved the submitted version.
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Mo, L., Li, R., He, C. et al. Hedgehog pathway is negatively regulated during the development of Drosophila melanogaster PheRS-m (Drosophila homologs gene of human FARS2) mutants. Human Cell 36, 121–131 (2023). https://doi.org/10.1007/s13577-022-00796-0
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DOI: https://doi.org/10.1007/s13577-022-00796-0