Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A.
Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A.
复制标题
爆发丝线激活会逆转鼠CMT2A中的神经肌肉功能障碍。
DOI：
10.7554/elife.61119
复制
发表时间：
2020-10-19
期刊：
影响因子：
7.7
通讯作者：
Dorn GW 2nd
中科院分区：
文献类型：
--
作者：
Franco A;Dang X;Walton EK;Ho JN;Zablocka B;Ly C;Miller TM;Baloh RH;Shy ME;Yoo AS;Dorn GW 2nd
夏科-玛丽-图思病 2A 型 (CMT2A) 是一种无法治疗的儿童周围神经病，由线粒体融合蛋白线粒体融合蛋白 (MFN) 2 突变引起。在这里，内源性正常线粒体融合蛋白的药理激活克服了 CMT2A 突变体在重编程人类患者运动神经元中的显着抑制作用，逆转了标志性线粒体停滞和碎片，与因果 MFN2 突变无关。在表达人 MFN2 T105M 的小鼠中，用小分子 MiM111 间歇性激活线粒体融合蛋白，使 CMT2A 神经肌肉功能障碍正常化，逆转治疗前轴突和骨骼肌细胞萎缩，并通过增加外周轴突内的线粒体运输和促进体内线粒体定位到神经肌肉连接突触来增强轴突再生。 MiM111 处理的 MFN2 T105M 小鼠神经元表现出加速的原代生长和更大的轴突切除后再生，与增强的线粒体运动有关。 MiM111是CMT2A的第一个临床前候选药物。 2A 型腓骨肌萎缩症是一种罕见的遗传性儿童疾病，神经细胞的死亡会导致手臂和腿部肌肉丧失，从而导致永久性残疾。目前尚无已知的治疗方法。在这种形式的 CMT 中，一种称为线粒体融合蛋白 2 的蛋白质的突变会损害细胞内称为线粒体的结构。线粒体产生大部分化学能来为细胞提供动力，但当线粒体融合蛋白 2 发生突变时，线粒体的健康状况就会较差，无法在细胞内移动，从而剥夺了细胞的能量。这尤其会导致从脊髓延伸到手臂和腿部肌肉的长神经细胞出现问题。现在，佛朗哥、丹等人。想看看重新激活线粒体融合蛋白 2 是否可以纠正线粒体损伤并恢复与肌肉的神经连接。研究人员在实验室中从患有 CMT2A 的人和该疾病的小鼠模型中取出神经细胞后，测试了一种名为线粒体融合蛋白激活剂的新型药物。线粒体融合蛋白激活剂改善了人和小鼠神经细胞中线粒体的结构、适应性和运动。弗朗哥，当等人。然后在带有 CMT2A 突变的小鼠身上测试了该药物，发现它还可以刺激神经再生，从而逆转肌肉损失和无力。这是科学家首次成功逆转 CMT2A 对小鼠和人类神经细胞的影响。然而，这些药物在广泛提供给患者之前仍需要经过广泛的临床试验测试。如果获得批准，线粒体融合蛋白激活剂也可能对患有其他损害线粒体的遗传性疾病的患者有益。
Charcot–Marie-Tooth disease type 2A (CMT2A) is an untreatable childhood peripheral neuropathy caused by mutations of the mitochondrial fusion protein, mitofusin (MFN) 2. Here, pharmacological activation of endogenous normal mitofusins overcame dominant inhibitory effects of CMT2A mutants in reprogrammed human patient motor neurons, reversing hallmark mitochondrial stasis and fragmentation independent of causal MFN2 mutation. In mice expressing human MFN2 T105M, intermittent mitofusin activation with a small molecule, MiM111, normalized CMT2A neuromuscular dysfunction, reversed pre-treatment axon and skeletal myocyte atrophy, and enhanced axon regrowth by increasing mitochondrial transport within peripheral axons and promoting in vivo mitochondrial localization to neuromuscular junctional synapses. MiM111-treated MFN2 T105M mouse neurons exhibited accelerated primary outgrowth and greater post-axotomy regrowth, linked to enhanced mitochondrial motility. MiM111 is the first pre-clinical candidate for CMT2A. Charcot-Marie-Tooth disease type 2A is a rare genetic childhood disease where dying back of nerve cells leads to muscle loss in the arms and legs, causing permanent disability. There is no known treatment. In this form of CMT, mutations in a protein called mitofusin 2 damage structures inside cells known as mitochondria. Mitochondria generate most of the chemical energy to power a cell, but when mitofusin 2 is mutated, the mitochondria are less healthy and are unable to move within the cell, depriving the cells of energy. This particularly causes problems in the long nerve cells that stretch from the spinal cord to the arm and leg muscles. Now, Franco, Dang et al. wanted to see whether re-activating mitofusin 2 could correct the damage to the mitochondria and restore the nerve connections to the muscles. The researchers tested a new class of drug called a mitofusin activator on nerve cells grown in the laboratory after being taken from people suffering from CMT2A, and also from a mouse model of the disease. Mitofusin activators improved the structure, fitness and movement of mitochondria in both human and mice nerve cells. Franco, Dang et al. then tested the drug in the mice with a CMT2A mutation and found that it could also stimulate nerves to regrow and so reverse muscle loss and weakness. This is the first time scientists have succeeded to reverse the effects of CMT2A in nerve cells of mice and humans. However, these drugs will still need to go through extensive testing in clinical trials before being made widely available to patients. If approved, mitofusin activators may also be beneficial for patients suffering from other genetic conditions that damage mitochondria.