Project description:To determine transcriptome changes in pre-disease onset spinal cord induced by the GarsP278KY mutation. How mutations in broadly expressed housekeeping genes lead to neurodegeneration in specific cell types remains unclear. Mutations in ubiquitously expressed tRNA synthetase genes cause axonal peripheral neuropathy, accounting for at least six forms of Charcot-Marie-Tooth disease. Genetic evidence in mouse and Drosophila models suggests a neomorphic gain-of-function mechanism. Here, we use in vivo, cell-type-specific transcriptional and translational profiling of affected peripheral neurons to show that mutant tRNA synthetases impair translation and activate the integrated stress response (ISR) through the sensor kinase, GCN2. The chronic activation of the ISR contributes to the pathophysiology, and genetic deletion of Gcn2 alleviates the peripheral neuropathy. The activation of GCN2 by tRNA synthetase mutations indicates their neomorphic activity is still related to translation and suggests inhibiting GCN2 or the ISR as a therapeutic strategy.
Project description:We examined the effects of ICG-001 on gene expression in Mel202 uveal melanoma (UM) cells. ICG-001 exerted strong antiproliferative activity against UM cells, leading to cell cycle arrest, apoptosis, and inhibition of migration. Global gene expression profiling revealed strong suppression of genes associated with cell cycle proliferation, DNA replication, and G1/S transition. Gene set enrichment analysis revealed that ICG-001 suppressed Wnt, mTOR, and MAPK signaling. Strikingly, ICG-001 suppressed the expression of genes associated with UM aggressiveness, including CDH1, CITED1, EMP1, EMP3, SDCBP, and SPARC. Notably, the transcriptomic footprint of ICG-001, when applied to a UM patient dataset, was associated with better clinical outcome. Lastly, ICG-001 exerted anticancer activity against a UM tumor xenograft in mice.