Transcriptomic gene-network analysis for neurotoxicity and drug repurposing

<p>Chun-Yu Chuang, Yuh-Jeen Huang, Ho-Chen Lin and Chun-Wei Yang</p>

Transcriptomic gene-network analysis for neurotoxicity and drug repurposing

Chun-Yu Chuang, Yuh-Jeen Huang, Ho-Chen Lin and Chun-Wei Yang

National Tsing Hua University, Taiwan

: J Forensic Toxicol Pharmacol

Abstract

Our study established a research scheme of integrative transcriptomic analysis for investigating the neurodegenerative toxicity of silver nanoparticles (AgNPs) and applying to explore drug repurposing of spinal muscular atrophy (SMA). The transcriptomic analysis of mouse brain neural cells after AgNPs exposure found that the gene expressions of C-X-C motif chemokine 13 (CXCL13), macrophage receptor with collagenous structure (MARCO) and glutathione synthetase (GSS) were induced for inflammatory response and oxidative stress, and additionally amyloid precursor protein (APP) was induced and neprilysin (NEP) and low-density lipoprotein receptor (LDLR) were reduced for Aβ plaque production and aggregation. It suggested AgNPs could alter gene expressions of Aβ deposition potentially to cause neurodegenerative disorder (Alzheimer's disease) progression underlying Aβ deposition. On the other hand, the 39 human microarray datasets across different types of SMA tissues were used for the integrative transcriptomic analysis, which identified TNFα-BMP4-SERPINE1-GATA6 pathway associated with disease severity. Down-regulation of bone morphogenetic protein 4 (BMP4) may be one of the key points in SMA pathogenesis. BMP4 expression can be induced by cholesterol lowering drug Atorvastatin. SMA mice receiving Atorvastatin treatment prolonged the lifespan, increased body weight, improved motor coordination and exhibited reduced motor neuron degeneration and muscle and cardiac atrophy. In conclusion, the integrative transcriptomic analysis is a useful tool for toxicological effect evaluation and drug repurposing.