Lai Chen, Xie Chengsong, McCormack Stefanie G, Chiang Hsueh-Cheng, Michalak Marta K, Lin Xian, Chandran Jayanth, Shim Hoon, Shimoji Mika, Cookson Mark R, Huganir Richard L, Rothstein Jeffrey D, Price Donald L, Wong Philip C, Martin Lee J, Zhu J Julius, Cai Huaibin
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892-3707, USA.
J Neurosci. 2006 Nov 8;26(45):11798-806. doi: 10.1523/JNEUROSCI.2084-06.2006.
Amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disease is caused by a selective loss of motor neurons. One form of juvenile onset autosomal recessive ALS (ALS2) has been linked to the loss of function of the ALS2 gene. The pathogenic mechanism of ALS2-deficiency, however, remains unclear. To further understand the function of alsin that is encoded by the full-length ALS2 gene, we screened proteins interacting with alsin. Here, we report that alsin interacted with glutamate receptor interacting protein 1 (GRIP1) both in vitro and in vivo, and colocalized with GRIP1 in neurons. In support of the physiological interaction between alsin and GRIP1, the subcellular distribution of GRIP1 was altered in ALS2(-/-) spinal motor neurons, which correlates with a significant reduction of AMPA-type glutamate receptor subunit 2 (GluR2) at the synaptic/cell surface of ALS2(-/-) neurons. The decrease of calcium-impermeable GluR2-containing AMPA receptors at the cell/synaptic surface rendered ALS2(-/-) neurons more susceptible to glutamate receptor-mediated neurotoxicity. Our findings reveal a novel function of alsin in AMPA receptor trafficking and provide a novel pathogenic link between ALS2-deficiency and motor neuron degeneration, suggesting a protective role of alsin in maintaining the survival of motor neurons.
肌萎缩侧索硬化症（ALS）是最常见的成人发病型运动神经元疾病，由运动神经元的选择性丧失引起。青少年型常染色体隐性遗传性ALS（ALS2）的一种形式与ALS2基因功能丧失有关。然而，ALS2缺陷的致病机制仍不清楚。为了进一步了解由全长ALS2基因编码的alsin的功能，我们筛选了与alsin相互作用的蛋白质。在此，我们报告alsin在体外和体内均与谷氨酸受体相互作用蛋白1（GRIP1）相互作用，并在神经元中与GRIP1共定位。为支持alsin与GRIP1之间的生理相互作用，GRIP1的亚细胞分布在ALS2（-/-）脊髓运动神经元中发生改变，这与ALS2（-/-）神经元突触/细胞表面的AMPA型谷氨酸受体亚基2（GluR2）显著减少相关。细胞/突触表面含钙不渗透GluR2的AMPA受体减少使ALS2（-/-）神经元更容易受到谷氨酸受体介导的神经毒性作用。我们的研究结果揭示了alsin在AMPA受体转运中的新功能，并提供了ALS2缺陷与运动神经元变性之间的新致病联系，表明alsin在维持运动神经元存活中具有保护作用。
