对低剂量聚乙二醇化IGF1治疗不敏感的SMARD1小鼠模型的初级运动神经元分化缺陷

Rare diseases (Austin, Tex.) Pub Date : 2014-06-10 eCollection Date: 2014-01-01 DOI:10.4161/rdis.29415
Frank Krieger, Friedrich Metzger, Sibylle Jablonka
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引用次数: 3

摘要

肌肉萎缩和膈肌麻痹是脊髓性肌萎缩伴呼吸窘迫1型(SMARD1)的临床特征,在神经肌肉变性(Nmd(2J))小鼠中有很好的表现,模拟了SMARD1的幼年型。在人类和小鼠中,IGHMBP2基因的突变都会导致运动神经元变性。我们之前可以证明,用聚乙二醇偶联的IGF1变体(PEG-IGF1)治疗可以改善运动功能,同时减少腓肠肌和膈肌的纤维变性,但对运动神经元的存活没有有益的影响。这些数据提出了细胞自主疾病机制导致ighmbp2缺陷运动神经元功能障碍和丧失的问题。对原发性ighmbp2缺陷运动神经元的分析显示分化缺陷,如自发Ca(2+)瞬态减少和轴突伸长改变,而PEG-IGF1无法补偿这一缺陷。这表明运动神经元退行性变的一个不依赖于IGF1的机制,除了IGF1之外,还需要治疗方法。
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Differentiation defects in primary motoneurons from a SMARD1 mouse model that are insensitive to treatment with low dose PEGylated IGF1.

Muscle atrophy and diaphragmatic palsy are the clinical characteristics of spinal muscular atrophy with respiratory distress type 1 (SMARD1), and are well represented in the neuromuscular degeneration (Nmd(2J) ) mouse, modeling the juvenile form of SMARD1. Both in humans and mice mutations in the IGHMBP2 gene lead to motoneuron degeneration. We could previously demonstrate that treatment with a polyethylene glycol-coupled variant of IGF1 (PEG-IGF1) improves motor functions accompanied by reduced fiber degeneration in the gastrocnemius muscle and the diaphragm, but has no beneficial effect on motoneuron survival. These data raised the question which cell autonomous disease mechanisms contribute to dysfunction and loss of Ighmbp2-deficient motoneurons. An analysis of primary Ighmbp2-deficient motoneurons exhibited differentiation deficits such as reduced spontaneous Ca(2+) transients and altered axon elongation, which was not compensated by PEG-IGF1. This points to an IGF1 independent mechanism of motoneuron degeneration that deserves treatment approaches in addition to IGF1.

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