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. 2019 Mar 5;9:3539. doi: 10.1038/s41598-019-40118-3

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Dysregulation of p53 associated DNA repair and WNT genes and DNA damage in SBMA mice. (A) The mRNA expression of p53 target genes tuberous sclerosis complex 2 (Tsc2), sestrin 1 (Sesn1), sestrin 2 (Sesn2), AMP-activated protein kinase (Ampkb), phosphatase and tensin homolog (Pten), IGF-binding protein 3 (Igfbp3) and growth arrest and DNA damage-inducible 45 (Gadd45) was examined in E13 AR100 and control AR20 motor neurons cultures. Sesn1, Sesn2, Ampkb, Igfbp3, Gadd45 and Ho-1 were downregulated. (B) The WNT inhibitory gene Dkk1 was increased, with no change in Dkk2 and Dkk3 expression. (C) The expression of p53 target genes Sesn2, Ampkb, Igfbp1, Gadd45, Dram1 and p53 associated genes Tp63 (p63) and Atr was downregulated in spinal cord of AR100 relative to control AR20 presymptomatic mice, at 3 months of age. (D) Dkk1 was downregulated in presymptomatic AR100 mice. qPCR data are displayed as mean ± SEM and are representative of three independent experiments. Statistical analysis was performed using a two sample t-test (n ≥ 3, *P < 0.05). (E) A p53 PCR array was used to determine the expression of genes associated with the p53 pathway from spinal cord of AR20 and AR100 presymptomatic mice of 3 months of age. Myod1 and Traf1 were increased, while Egfr, Ccne1, Pmaip1, Mdm2, Kras, Xrcc5 and Mcl1 were significantly downregulated. qPCR data are displayed as mean ± SEM. Statistical analysis was performed using a two sample t-test (*P < 0.05). (F) Ventral horn spinal cord was immunostained with γ-H2AX (a marker of DNA damage) and β-III tubulin . There was evidence of γ-H2AX foci in motor neurons of 12 month old AR100 mice. Scale bars represent 10 μm.