Neuron-targeted caveolin-1 improves neuromuscular function and extends survival in SOD1G93A mice
Neuron-targeted caveolin-1 improves neuromuscular function and extends survival in SOD1G93A mice
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DOI：
10.1096/fj.201802652rr
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发表时间：
2019-06-01
期刊：
影响因子：
4.8
通讯作者：
Head, Brian P.
中科院分区：
文献类型：
--
作者：
Sawada, Atsushi;Wang, Shanshan;Head, Brian P.
保护运动神经元或恢复功能性运动神经可塑性的干预措施可能会延长肌萎缩侧索硬化症(ALS)的寿命。神经营养素的输送可能会使退化的运动神经元复苏，但这种方法依赖于神经营养素受体(NTR)对质膜信号微域的适当亚细胞定位，称为膜/脂筏(MLRs)。我们先前的研究表明，突触素驱动的小窝蛋白-1(Cav-1)(SynCav1)的过表达增加了NTR[如受体酪氨酸激酶B(TrkB)]的MLR定位，促进了海马区突触和神经可塑性，并显著改善了老年小鼠的学习和记忆。本研究将SynCav1转基因阳性(SynCav1(+))小鼠与突变型人超氧化物歧化酶甘氨酸到丙氨酸点突变93位氨基酸(hSOD1(G93A))的ALS小鼠模型进行杂交。与hSOD1(G93A)/SynCav1(+)小鼠相比，hSOD1(G93A)/SynCav1(+)小鼠体重更大，存活时间更长，运动功能更好。对hSOD1(G93A)/SynCav1(+)脊髓的显微镜分析显示，脊髓α运动神经元和线粒体形态都保存了下来。此外，hSOD1(G93A)/SynCav1(+)脊髓有更多的MLRs(霍乱毒素B亚单位阳性)和MLR相关的TrkB和Cav-1蛋白表达。这些发现表明，SynCav1可能通过保留或恢复NTR的表达和MLRs的定位来延缓ALS小鼠模型的疾病进展。-Sawada，A.，Wang，S.，Jian，M.，Leem，J.，Wackerbarth，J.，Egawa，J.，Schilling，J.M.，Platoshyn，O.，Zemljic-Harpf，A.，Roth，D.M.，Patel，H.，Patel，P.M.，Marsala，M.，Head，B.P.Neuron靶向Cavelin-1改善SOD1(G93A)小鼠的神经肌肉功能并延长存活时间。
Interventions that preserve motor neurons or restore functional motor neuroplasticity may extend longevity in amyotrophic lateral sclerosis (ALS). Delivery of neurotrophins may potentially revive degenerating motor neurons, yet this approach is dependent on the proper subcellular localization of neurotrophin receptor (NTR) to plasmalemmal signaling microdomains, termed membrane/lipid rafts (MLRs). We previously showed that overexpression of synapsin-driven caveolin-1 (Cav-1) (SynCav1) increases MLR localization of NTR [e.g., receptor tyrosine kinase B (TrkB)], promotes hippocampal synaptic and neuroplasticity, and significantly improves learning and memory in aged mice. The present study crossed a SynCav1 transgene-positive (SynCav1(+)) mouse with the mutant human superoxide dismutase glycine to alanine point mutation at amino acid 93 (hSOD1(G93A)) mouse model of ALS. When compared with hSOD1(G93A), hSOD1(G93A)/SynCav1(+) mice exhibited greater body weight and longer survival as well as better motor function. Microscopic analyses of hSOD1(G93A)/SynCav1(+) spinal cords revealed preserved spinal cord alpha-motor neurons and preserved mitochondrial morphology. Moreover, hSOD1(G93A)/SynCav1(+) spinal cords contained more MLRs (cholera toxin subunit B positive) and MLR-associated TrkB and Cav-1 protein expression. These findings demonstrate that SynCav1 delays disease progression in a mouse model of ALS, potentially by preserving or restoring NTR expression and localization to MLRs.-Sawada, A., Wang, S., Jian, M., Leem, J., Wackerbarth, J., Egawa, J., Schilling, J. M., Platoshyn, O., Zemljic-Harpf, A., Roth, D. M., Patel, H. H., Patel, P. M., Marsala, M., Head, B. P. Neuron-targeted caveolin-1 improves neuromuscular function and extends survival in SOD1(G93A) mice.