DOK7 gene therapy suppresses motor nerve terminal degeneration at the NMJ in ALS mice DOK7 gene therapy suppresses motor nerve terminal degeneration at.

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DOK7 gene therapy suppresses motor nerve terminal degeneration at the NMJ in ALS mice DOK7 gene therapy suppresses motor nerve terminal degeneration at the NMJ in ALS mice AForelimb grip strength of wild‐type (WT) mice and that of control and AAV‐D7 treatment groups of ALS mice at P84 (WT, n = 5 mice; control group, n = 5 mice; treatment group, n = 6 mice). Values are means ± SEM. **P = 0.0016 (WT vs. control group) and 0.0003 (WT vs. treatment group) by one‐way analysis of variance (ANOVA) with Bonferroni's post hoc test. n.s., not significant.BThe difference in cycle threshold (ΔCt) between the human SOD1‐G93A transgene and the reference mouse apob gene. To calculate the human transgene level, the ΔCt value of hSOD1 was subtracted from the ΔCt value of apob (control group, n = 5 mice; treatment group, n = 6 mice).C–GWT or ALS mice treated or not with 1.2 × 1012 vg of AAV‐D7 at P90 were subjected to the following assays at P120. Tyrosine phosphorylation of MuSK or AChR in the hind‐limb muscle. MuSK or AChRβ1 subunit (AChRβ1) immunoprecipitates (IP) from whole‐tissue lysates (WTLs) of the hind‐limb muscle were immunoblotted for phosphotyrosine (pY), MuSK, and AChRβ1. WTLs were blotted for Dok‐7‐EGFP, human SOD1, and GAPDH (C). Whole‐mount staining of NMJs on the diaphragm muscle. Motor nerve terminals (green) and postsynaptic AChRs (red) were stained with anti‐synapsin‐1 antibodies and α‐bungarotoxin, respectively. Expression of Dok‐7‐EGFP fusion protein (gray) was monitored by EGFP. Scale bars, 50 μm. NT, not treated (D). The size of AChR cluster (E), the size of motor nerve terminal (F), and innervation ratio (G) (WT‐NT, n = 5 mice; ALS‐NT, n = 5 mice; ALS‐AAV‐D7, n = 6 mice). Values are means ± SD. (E) ***P < 0.0001; (F) **P = 0.0077, ***P = 0.0001; (G) *P = 0.0134, ***P < 0.0001 by one‐way ANOVA with Dunnett's post hoc test.Source data are available online for this figure. Sadanori Miyoshi et al. EMBO Mol Med. 2017;emmm.201607298 © as stated in the article, figure or figure legend