Shared resistance to aging and ALS in neuromuscular junctions of specific muscles.
Shared resistance to aging and ALS in neuromuscular junctions of specific muscles.
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DOI：
10.1371/journal.pone.0034640
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Sanes JR
中科院分区：
文献类型：
--
作者：
Valdez G;Tapia JC;Lichtman JW;Fox MA;Sanes JR
正常的衰老和神经退行性疾病都会导致突触的结构和功能改变。比较一般相似但对损伤反应不同的突触，可以为发现易感性或抵抗损伤的机制提供基础。在这里，我们分析了16只小鼠肌肉的骨骼神经肌肉接头（NMJ），以寻求这种差异。我们发现，肌肉对衰老的反应有三种。在某些情况下，包括大多数肢体和躯干肌肉，与年龄相关的NMJ变化在出生后的第二年是渐进和广泛的。其他肌肉中的NMJ，如眼外肌，对变化有着惊人的抵抗力。第三组肌肉，包括几块面部表情肌肉和肛门外括约肌，会随着年龄的增长而衰老，但要到出生后的第三年。我们问是否敏感和阻力肌肉不同的rostrocaudal或proximodistal位置，神经支配的来源，运动单位的大小，或纤维类型的组成。在这些因素中，脑干运动神经元的肌肉神经支配与年龄相关性下降的抵抗力相关性最好。最后，我们比较了正常衰老肌肉与肌萎缩侧索硬化症（ALS）小鼠模型中的突触改变。在这两种条件下，抗性和易感性模式显著相关。此外，老年肌肉中NMJ的损伤与CRMP 4a和TDP-43的表达和分布改变相关，这两者在受ALS影响的运动神经元中都发生了改变。总之，这些结果揭示了衰老和ALS之间新的结构，区域和分子相似之处。
Normal aging and neurodegenerative diseases both lead to structural and functional alterations in synapses. Comparison of synapses that are generally similar but respond differently to insults could provide the basis for discovering mechanisms that underlie susceptibility or resistance to damage. Here, we analyzed skeletal neuromuscular junctions (NMJs) in 16 mouse muscles to seek such differences. We find that muscles respond in one of three ways to aging. In some, including most limb and trunk muscles, age-related alterations to NMJs are progressive and extensive during the second postnatal year. NMJs in other muscles, such as extraocular muscles, are strikingly resistant to change. A third set of muscles, including several muscles of facial expression and the external anal sphinter, succumb to aging but not until the third postnatal year. We asked whether susceptible and resistant muscles differed in rostrocaudal or proximodistal position, source of innervation, motor unit size, or fiber type composition. Of these factors, muscle innervation by brainstem motor neurons correlated best with resistance to age-related decline. Finally, we compared synaptic alterations in normally aging muscles to those in a mouse model of amyotrophic lateral sclerosis (ALS). Patterns of resistance and susceptibility were strikingly correlated in the two conditions. Moreover, damage to NMJs in aged muscles correlated with altered expression and distribution of CRMP4a and TDP-43, which are both altered in motor neurons affected by ALS. Together, these results reveal novel structural, regional and molecular parallels between aging and ALS.
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