Veterans Affairs San Diego Healthcare System, San Diego, California, USA.
Department of Anesthesiology, School of Medicine, University of California-San Diego, La Jolla, California, USA.
FASEB J. 2019 Jun;33(6):7545-7554. doi: 10.1096/fj.201802652RR. Epub 2019 Mar 20.
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) () increases MLR localization of NTR [, 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) mouse model of ALS. When compared with hSOD1, hSOD1/SynCav1 mice exhibited greater body weight and longer survival as well as better motor function. Microscopic analyses of hSOD1/SynCav1 spinal cords revealed preserved spinal cord α-motor neurons and preserved mitochondrial morphology. Moreover, hSOD1/SynCav1 spinal cords contained more MLRs (cholera toxin subunit B positive) and MLR-associated TrkB and Cav-1 protein expression. These findings demonstrate that 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 mice.
干预措施，可保存运动神经元或恢复功能性运动神经可塑性，可能会延长肌萎缩侧索硬化症（ALS）的寿命。神经营养因子的传递可能会使退化的运动神经元复活，但这种方法依赖于神经营养因子受体（NTR）向质膜信号微区（称为膜/脂筏（MLR））的适当亚细胞定位。我们之前的研究表明，突触素驱动的小窝蛋白-1（Cav-1）的过表达（SynCav1）增加了 NTR [，受体酪氨酸激酶 B（TrkB）]的 MLR 定位，促进了海马突触和神经可塑性，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）小鼠与肌萎缩侧索硬化症的突变人类超氧化物歧化酶甘氨酸至丙氨酸点突变（hSOD1）模型小鼠杂交。与 hSOD1 相比，hSOD1/SynCav1 小鼠表现出更大的体重和更长的存活时间以及更好的运动功能。hSOD1/SynCav1 脊髓的显微镜分析显示，α-运动神经元得到了保存，线粒体形态得到了保存。此外，hSOD1/SynCav1 脊髓含有更多的 MLR（霍乱毒素亚单位 B 阳性）和 MLR 相关的 TrkB 和 Cav-1 蛋白表达。这些发现表明，SynCav1 延迟了 ALS 模型小鼠的疾病进展，可能是通过保存或恢复 NTR 的表达和定位到 MLR。-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.。神经元靶向小窝蛋白-1可改善肌萎缩侧索硬化症 SOD1 小鼠的神经肌肉功能并延长其生存期。
