Document Type
Article
Publication Date
2018
Keywords
Alzheimer’s disease, Amyotrophic lateral sclerosis, Extracellular matrix, Hedgehog, Huntington’s disease, Neurodegenerative disease, Notch, Parkinson’s disease, RNA-seq, Transcriptome
Digital Object Identifier (DOI)
https://doi.org/10.1186/s40035-018-0135-7
Abstract
Background: Amyotrophic lateral sclerosis (ALS) is currently an incurable disease without highly effective pharmacological treatments. The 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 profile. GM6 is hypothesized to bolster neuron survival through the multi-target regulation of developmental pathways, but mechanisms of action are not fully understood.
Methods: 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 (FDR < 0.10). Early (6 h) responses included up-regulation of Notch and hedgehog signaling components, with increased expression of developmental genes mediating neurogenesis and axon growth. Prolonged GM6 treatment (24 and 48 h) altered the expression of genes contributing to cell adhesion and the extracellular matrix. GM6 further down-regulated the expression of genes associated with mitochondria, inflammatory responses, mRNA processing and chromatin organization. GM6-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 factors. Such 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 (FDR < 0.10), which were known to function in neurogenesis, axon guidance and the intrinsic apoptosis pathway.
Conclusions: Our findings support the hypothesis that GM6 acts through developmental-stage pathways to influence neuron survival. Gene expression responses were consistent with neurotrophic effects, ECM modulation, and activation of the Notch and hedgehog neurodevelopmental pathways. This multifaceted mechanism of action is unique among existing ALS drug candidates and may be applicable to multiple neurodegenerative diseases.
Rights Information
This work is licensed under a Creative Commons Attribution 4.0 License.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Translational Neurodegeneration, v. 7, art. 30
Scholar Commons Citation
Swindell, William R.; Bojanowski, Krzysztof; Kindy, Mark S.; Chau, Raymond M. W.; and Ko, Dorothy, "GM604 Regulates Developmental Neurogenesis Pathways and the Expression of Genes Associated with Amyotrophic Lateral Sclerosis" (2018). Pharmacy Faculty Publications. 53.
https://digitalcommons.usf.edu/pharm_facpub/53
