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Translational Neurodegeneration
Published in: Translational Neurodegeneration 1/2018

Open Access 01-12-2018 | Research

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

Authors: William R. Swindell, Krzysztof Bojanowski, Mark S. Kindy, Raymond M. W. Chau, Dorothy Ko

Published in: Translational Neurodegeneration | Issue 1/2018

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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.
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Metadata
Title
GM604 regulates developmental neurogenesis pathways and the expression of genes associated with amyotrophic lateral sclerosis
Authors
William R. Swindell
Krzysztof Bojanowski
Mark S. Kindy
Raymond M. W. Chau
Dorothy Ko
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Translational Neurodegeneration / Issue 1/2018
Electronic ISSN: 2047-9158
DOI
https://doi.org/10.1186/s40035-018-0135-7

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