Jablonka S, Bandilla M, Wiese S, Bühler D, Wirth B, Sendtner M, Fischer U
Klinische Forschergruppe Neuroregeneration, Department of Neurology, University of Würzburg, Josef-Schneider-Strasse 11, D-97080 Würzburg, Germany.
Hum Mol Genet. 2001 Mar 1;10(5):497-505. doi: 10.1093/hmg/10.5.497.
Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by the degeneration of motor neurons in the spinal cord. The disease is caused by mutations of the survival of motor neuron 1 gene (SMN1), resulting in a reduced production of functional SMN protein. A major question unanswered thus far is why reduced amounts of ubiquitously expressed SMN protein specifically cause the degeneration of motor neurons without affecting other somatic cell types. In a first attempt to address this issue we have investigated the Smn interacting protein 1 (Sip1), with an emphasis on its developmental expression and subcellular distribution in spinal motor neurons in relation to Smn. By confocal immunofluorescence studies we provide evidence that a significant amount of Smn does not co-localize with Sip1 in neurites of motor neurons, indicating that Smn may exert motor neuron-specific functions that are not dependent on Sip1. Sip1 is highly expressed in the spinal cord during early development and expression decreases in parallel with Smn during postnatal development. Strikingly, reduced production of Smn as observed in cell lines derived from SMA patients or in a mouse model for SMA coincides with a simultaneous reduction of Sip1. The finding that expression of Sip1 and Smn is tightly co-regulated, together with the unique localization of Smn in neurites, may help in understanding the motor neuron-specific defects observed in SMA patients.
脊髓性肌萎缩症（SMA）是一种神经肌肉疾病，其特征是脊髓中的运动神经元退化。该疾病由运动神经元存活1基因（SMN1）突变引起，导致功能性SMN蛋白产量减少。到目前为止尚未解决的一个主要问题是，为什么普遍表达的SMN蛋白量减少会特异性地导致运动神经元退化，而不影响其他体细胞类型。为了解决这个问题，我们首次研究了Smn相互作用蛋白1（Sip1），重点关注其在脊髓运动神经元中的发育表达和亚细胞分布与Smn的关系。通过共聚焦免疫荧光研究，我们提供了证据表明，大量的Smn在运动神经元的神经突中不与Sip1共定位，这表明Smn可能发挥不依赖于Sip1的运动神经元特异性功能。Sip1在早期发育期间在脊髓中高度表达，并且在出生后发育过程中其表达与Smn平行下降。引人注目的是，在源自SMA患者的细胞系或SMA小鼠模型中观察到的Smn产量降低与Sip1的同时降低相吻合。Sip1和Smn的表达紧密共调节这一发现，以及Smn在神经突中的独特定位，可能有助于理解在SMA患者中观察到的运动神经元特异性缺陷。
