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Transcriptome Evidence Reveals Mitochondrial Unfolded Protein Response Participate in SH-SY5Y Cells Exposed to

Shixuan Zhang1,2, Li Chen1,2, Tian Chen1,2

  • 1Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, 100069 Beijing, China.

Journal of Integrative Neuroscience
|September 22, 2022
PubMed
Abstract

Insights

Manganese (Mn) exposure causes neurotoxicity by altering gene expression and impacting pathways like MAPK signaling. Mitochondrial unfolded protein response (UPRMT) emerges as a key mechanism in Mn-induced neurodegeneration.

Area of Science:

  • Neuroscience
  • Toxicology
  • Molecular Biology
  • Genomics

Background:

  • Manganese (Mn) overexposure can cause neurodegenerative damage, mimicking Parkinson's disease (PD) symptoms through a condition known as manganism.
  • The transcriptomic alterations induced by toxic levels of manganese remain largely uncharacterized.
  • This study investigates Mn-induced changes in gene expression and signaling pathways in human neuroblastoma cells.

Purpose of the Study:

  • To explore candidate genes and signaling pathways affected by manganese exposure using RNA sequencing.
  • To identify key genes and pathways involved in manganese-induced neurotoxicity.
  • To elucidate the role of mitochondrial unfolded protein response (UPRMT) in manganese neurotoxicity.

Main Methods:

  • RNA sequencing (RNA-seq) was performed on human SH-SY5Y neuroblastoma cells exposed to manganese.
  • Differentially expressed genes (DEGs) were identified, and weighted gene co-expression network analysis (WGCNA) was used to find hub genes.
  • Pathway enrichment analyses (GO, KEGG) and quantitative reverse transcription PCR (qRT-PCR) were employed to validate findings, including UPRMT responses.

Main Results:

  • Manganese exposure resulted in 179 up-regulated and 681 down-regulated DEGs, with 73 DEGs linked to neurotoxicity.
  • Key affected pathways include MAPK signaling, unfolded protein response, longevity regulation, inflammatory bowel disease, and mitophagy.
  • Specific gene expression changes included increased ATF3 and CCL2, and decreased CHOP, CLPP, and LONP1 in a dose- and time-dependent manner.

Conclusions:

  • Manganese exposure significantly alters gene expression and impacts multiple cellular signaling pathways.
  • The study highlights the involvement of the mitochondrial unfolded protein response (UPRMT) as a critical factor in manganese-induced neurotoxicity.
  • UPRMT represents a novel target for understanding and potentially mitigating manganese neurotoxicity.
Keywords:
bioinformaticscandidate genesmanganesemitochondrial unfolded protein responseneurotoxicity

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