Mechanism of Neuromuscular Dysfunction in Krabbe Disease
Mechanism of Neuromuscular Dysfunction in Krabbe Disease
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DOI：
10.1523/jneurosci.2431-14.2015
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发表时间：
2015-01-28
影响因子：
5.3
通讯作者：
Bongarzone, Ernesto R.
中科院分区：
文献类型：
--
作者：
Cantuti-Castelvetri, Ludovico;Maravilla, Erick;Bongarzone, Ernesto R.
Krabbe病患者的骨骼肌萎缩是一种主要的衰弱表现，影响了他们的生活质量，限制了目前治疗的临床疗效。引发肌肉萎缩的致病机制尚不清楚。本研究使用小鼠（颤搐小鼠）和犬[球样细胞脑白质营养不良（GLD）犬]模型检查了有助于Krabbe病肌肉变性的结构、功能和代谢变化。肌肉变性，去神经支配，神经肌肉[神经肌肉接头（NMJ）]异常，和轴突死亡进行了研究，使用报告转基因twitcher-Thy 1.1-黄色荧光蛋白小鼠。我们发现突变肌肉有大量较小的肌肉纤维，没有再生的迹象。抽搐小鼠的肌肉生长缓慢而无力，最大力量下降。NMJ具有显著水平的活化的caspase-3，但有限的去神经支配。突变NMJ表现出突触前末梢的表面积减少和体积减小，神经控制降低，微型终板电位（MEPP）振幅增加，MEPP频率降低，上升和衰减速率常数增加。Twitcher和GLD狗的肌肉有显着的能力，以存储psychosine，神经毒素，积累在克拉布病。从机制上讲，肌肉缺陷涉及Akt途径的失活和蛋白酶体途径的激活。我们的工作表明，Krabbe病的肌肉功能障碍是由一种致病机制复合的，该机制至少涉及NMJ功能的失效、蛋白体降解的激活和Akt通路的减少。Akt是肌肉功能的关键，可能成为Krabbe病治疗的新靶点。
The atrophy of skeletal muscles in patients with Krabbe disease is a major debilitating manifestation that worsens their quality of life and limits the clinical efficacy of current therapies. The pathogenic mechanism triggering muscle wasting is unknown. This study examined structural, functional, and metabolic changes conducive to muscle degeneration in Krabbe disease using the murine (twitcher mouse) and canine [globoid cell leukodystrophy (GLD) dog] models. Muscle degeneration, denervation, neuromuscular [neuromuscular junction (NMJ)] abnormalities, and axonal death were investigated using the reporter transgenic twitcher-Thy1.1-yellow fluorescent protein mouse. We found that mutant muscles had significant numbers of smaller-sized muscle fibers, without signs of regeneration. Muscle growth was slow and weak in twitcher mice, with decreased maximum force. The NMJ had significant levels of activated caspase-3 but limited denervation. Mutant NMJ showed reduced surface areas and lower volumes of presynaptic terminals, with depressed nerve control, increased miniature endplate potential (MEPP) amplitude, decreased MEPP frequency, and increased rise and decay rate constants. Twitcher and GLD dog muscles had significant capacity to store psychosine, the neurotoxin that accumulates in Krabbe disease. Mechanistically, muscle defects involved the inactivation of the Akt pathway and activation of the proteasome pathway. Our work indicates that muscular dysfunction in Krabbe disease is compounded by a pathogenic mechanism involving at least the failure of NMJ function, activation of proteosome degradation, and a reduction of the Akt pathway. Akt, which is key for muscle function, mayconstitute a novel target to complement in therapies for Krabbe disease.