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Ribonuclease 4 protects neuron degeneration by promoting angiogenesis, neurogenesis, and neuronal survival under stress

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Abstract

Altered RNA processing is an underlying mechanism of amyotrophic lateral sclerosis (ALS). Missense mutations in a number of genes involved in RNA function and metabolisms are associated with ALS. Among these genes is angiogenin (ANG), the fifth member of the vertebrate-specific, secreted ribonuclease superfamily. ANG is an angiogenic ribonuclease, and both its angiogenic and ribonucleolytic activities are important for motor neuron health. Ribonuclease 4 (RNASE4), the fourth member of this superfamily, shares the same promoters with ANG and is co-expressed with ANG. However, the biological role of RNASE4 is unknown. To determine whether RNASE4 is involved in ALS pathogenesis, we sequenced the coding region of RNASE4 in ALS and control subjects and characterized the angiogenic, neurogenic, and neuroprotective activities of RNASE4 protein. We identified an allelic association of SNP rs3748338 with ALS and demonstrated that RNASE4 protein is able to induce angiogenesis in in vitro, ex vivo, and in vivo assays. RNASE4 also induces neural differentiation of P19 mouse embryonal carcinoma cells and mouse embryonic stem cells. Moreover, RNASE4 not only stimulates the formation of neurofilaments from mouse embryonic cortical neurons, but also protects hypothermia-induced degeneration. Importantly, systemic treatment with RNASE4 protein slowed weight loss and enhanced neuromuscular function of SOD1 G93A mice.

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Acknowledgments

This work was supported by National Institute of Health grant R01 NS 065237 (to GFH). GFH receives fund from NIH, ALS Therapy Alliance, and Harvard University Technology Development Accelerator Fund, Massachusetts Alzheimer Disease Research Center, and Tufts University CTSI program. RHB receives support from the National Institute for Neurological Disease and Stroke, the Angel Fund, the ALS Association, Project ALS, P2ALS. Pierre L. de Bourgknecht ALS Research Foundation, the Al-Athel ALS Foundation, and the ALS Therapy Alliance. We thank Robert Shapiro (Harvard Medical School) for helpful discussions on biochemical characterization of RNASE4, Helene F. Rosenberg (NIH/NIAID) for providing mouse Rnase4 expression plasmid, Jan Hofsteenge (Friedrich Miescher Institute, Switzerland) for providing pig RNASE4 expression plasmid.

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Authors and Affiliations

  1. Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Box 5069, Boston, MA, 02111, USA

    Shuping Li, Jinghao Sheng, Jamie K. Hu, Wenhao Yu, Hiroko Kishikawa, Miaofen G. Hu & Guo-fu Hu

  2. State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Shuping Li

  3. Institute of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China

    Jinghao Sheng & Zhengping Xu

  4. Division of Oral Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

    Kaori Shima

  5. Department of Laboratory Medicine, University of Washington, Seattle, WA, USA

    David Wu

  6. Department of Neurology, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA

    Winnie Xin & Katherine B. Sims

  7. Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA

    John E. Landers & Robert H. Brown Jr.

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  1. Shuping Li
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  2. Jinghao Sheng
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  14. Guo-fu Hu
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Correspondence to Guo-fu Hu.

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Li, S., Sheng, J., Hu, J.K. et al. Ribonuclease 4 protects neuron degeneration by promoting angiogenesis, neurogenesis, and neuronal survival under stress. Angiogenesis 16, 387–404 (2013). https://doi.org/10.1007/s10456-012-9322-9

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