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Purα Repaired Expanded Hexanucleotide GGGGCC Repeat Noncoding RNA-Caused Neuronal Toxicity in Neuro-2a Cells

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Abstract

Expanded hexanucleotide GGGGCC repeat in a noncoding region of C9ORF72 is the most common cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). However, its molecular pathogenesis remains unclear. In our previous study, the expanded GGGGCC repeats have been shown to be sufficient to cause neurodegeneration. In order to investigate the further role of expanded GGGGCC repeats in the neuron, the normal r(GGGGCC)3 and mutant-type expanded r(GGGGCC)30 expression vectors were transfected into Neuro-2a cells. Cell proliferation, dendrite development, and the proteins’ levels of microtubule-associated protein-2 (MAP2) and cyclin-dependent kinase-5 (CDK5) were used to evaluate the cell toxicity of GGGGCC repeats on Neuro-2a cells. The results were shown that expression of expanded GGGGCC repeats caused neuronal cell toxicity in Neuro-2a cells, enhanced the expression of pMAP2 and pCDK5. Moreover, overexpression of Purα repaired expanded GGGGCC repeat-inducing neuronal toxicity in Neuro-2a cells and reduced the expression of pMAP2 and pCDK5. In all, our findings suggested that the expanded GGGGCC repeats might cause neurodegeneration through destroyed neuron cells. And the GGGGCC repeat-induced neuronal cell toxicity was inhibited by upregulation of Purα. We inferred that Purα inhibits expanded GGGGCC repeat-inducing neurodegeneration, which might reveal a novel mechanism of neurodegenerative diseases ALS and FTD.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 31400916 and no. 81370942), Natural Science Foundation of Hubei Province (No. 2014CFB219), and Youth Science Chenguang Plan of Wuhan City (No. 2015071704011624). We thank professor Peng ** of Emory University for providing plasmids pEGFP-N1-(GGGGCC)3 and pEGFP-N1-(GGGGCC)30.

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Author notes

  1. Jianying Shen and Yu Zhang contributed equally to this work.

Authors and Affiliations

  1. Division of Histology and Embryology, Department of Anatomy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Jianying Shen, Yu Zhang & Honglian Li

  2. Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, China

    Shi Zhao, Hong Mao, Zhong**g Wang & Zihui Xu

  3. Key Laboratory for Molecular Diagnosis of Hubei Province, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, China

    Zihui Xu

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  1. Jianying Shen
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  2. Yu Zhang
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  4. Hong Mao
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  5. Zhong**g Wang
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Correspondence to Honglian Li or Zihui Xu.

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Highlights:

Expanded rGGGGCC repeats caused neuronal cell toxicity in Neuro-2a cells

Expanded rGGGGCC repeats reduced neuronal development-related proteins and destroyed structure of neuron

Purα expression repaired rGGGGCC repeats-induced neuronal cell toxicity

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Shen, J., Zhang, Y., Zhao, S. et al. Purα Repaired Expanded Hexanucleotide GGGGCC Repeat Noncoding RNA-Caused Neuronal Toxicity in Neuro-2a Cells. Neurotox Res 33, 693–701 (2018). https://doi.org/10.1007/s12640-017-9803-0

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  • DOI: https://doi.org/10.1007/s12640-017-9803-0

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