Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosis
Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosis
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DOI：
10.1073/pnas.0609411103
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发表时间：
2006-12-19
影响因子：
11.1
通讯作者：
Kaspar, Brian K.
中科院分区：
文献类型：
--
作者：
Miller, Timothy M.;Kim, Soo H.;Kaspar, Brian K.
肌萎缩性侧索硬化症（ALS）是一种由运动神经元过早死亡引起的致命的进行性麻痹。遗传形式是由普遍表达的超氧化物歧化酶（SOD1）的显性突变引起的。运动神经元内SOD1突变体的表达是疾病发病和早期的决定因素，小胶质细胞内突变体的积累加速了疾病的进展。肌肉也可能是毒性的主要来源，因为运动轴突从突触连接到肌肉的收缩是最早的症状前事件之一。为了测试肌肉与ALS的关系，转录介导的siRNA的病毒传递被证明可以抑制突变SOD1在肌肉中的积累，但不足以维持握力，而同时传递到运动神经元和肌肉是足够的。使用可删除的突变基因减少肌肉中的SOD1突变并不影响发病或存活。最后，腺相关病毒编码的foilistatin表达长期抑制肌肉生长抑制素，并产生肌肉质量、肌纤维数量和纤维直径的持续增加，但这些增加不影响生存。因此，sod1突变介导的肌肉损伤并不是ALS非细胞自主发病的重要因素，增加肌肉质量和力量对减缓疾病的发生或进展没有任何好处。
Amyotrophic lateral sclerosis (ALS) is a fatal, progressive paralysis arising from the premature death of motor neurons. An inherited form is caused by a dominant mutation in the ubiquitously expressed superoxide dismutase (SOD1). SOD1 mutant expression within motor neurons is a determinant of onset and early disease, and mutant accumulation within microglia accelerates disease progression. Muscle also is a likely primary source for toxicity, because retraction of motor axons from synaptic connections to muscle is among the earliest presymptomatic events. To test involvement of muscle in ALS, viral delivery of transcription-mediated siRNA is shown to suppress mutant SOD1 accumulation within muscle alone but to be insufficient to maintain grip strength, whereas delivery to both motor neurons and muscle is sufficient. Use of a deletable mutant gene to diminish mutant SOD1 from muscle did not affect onset or survival. Finally, foilistatin expression encoded by adeno-associated virus chronically inhibited myostatin and produced sustained increases in muscle mass, myofiber number, and fiber diameter, but these increases did not affect survival. Thus, SOD1-mutant-mediated damage within muscles is not a significant contributor to non-cell-autonomous pathogenesis in ALS, and enhancing muscle mass and strength provides no benefit in slowing disease onset or progression.