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GM604 regulates developmental neurogenesis pathways and the expression of genes associated with amyotrophic lateral sclerosis

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Translational Neurodegeneration 2018年第1期7卷 322-345页

作者： William R.Swindell Krzysztof Bojanowski Mark S.Kindy Raymond M.W.Chau Dorothy Ko Heritage College of Osteopathic Medicine Ohio UniversityAthensOHUSA Sunny BioDiscovery IncSanta PaulaCAUSA Department of Pharmaceutical Sciences College of PharmacyUniversity of South FloridaTampaFLUSA James A.Haley VAMC TampaFLUSA Genervon Biopharmaceuticals LLC PasadenaCAUSA

Background:Amyotrophic lateral sclerosis(ALS)is currently an incurable disease without highly effective pharmacological *** peptide drug GM604(GM6 or Alirinetide)was developed as a candidate ALS therapy,which has demonstrated safety and good drug-like properties with a favorable pharmacokinetic ***6 is hypothesized to bolster neuron survival through the multi-target regulation of developmental pathways,but mechanisms of action are not fully ***:This study used RNA-seq to evaluate transcriptome responses in SH-SY5Y neuroblastoma cells following GM6 treatment(6,24 and 48 h).Results:We identified 2867 protein-coding genes with expression significantly altered by GM6(FDRhedgehog signaling components,with increased expression of developmental genes mediating neurogenesis and axon *** GM6 treatment(24 and 48 h)altered the expression of genes contributing to cell adhesion and the extracellular ***6 further down-regulated the expression of genes associated with mitochondria,inflammatory responses,mRNA processing and chromatin ***6-increased genes were located near GC-rich motifs interacting with C2H2 zinc finger transcription factors,whereas GM6-decreased genes were located near AT-rich motifs associated with helix-turn-helix homeodomain *** motifs interacted with a diverse network of transcription factors encoded by GM6-regulated genes(STAT3,HOXD11,HES7,GLI1).We identified 77 ALS-associated genes with expression significantly altered by GM6 treatment(FDRhedgehog neurodevelopmental *** multif

关键词： Alzheimer’s disease Amyotrophic lateral sclerosis extracellular matrix,hedgehog Huntington’s disease Neurodegenerative disease Notch,Parkinson’s disease RNA-seq Transcriptome

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