Amyotrophic lateral sclerosis 2-deficiency leads to neuronal degeneration in amyotrophic lateral sclerosis through altered AMPA receptor trafficking

Chen Lai, Chengsong Xie, Stefanie G. McCormack, Hsueh Cheng Chiang, Marta K. Michalak, Xian Lin, Jayanth Chandran, Hoon Shim, Mika Shimoji, Mark R. Cookson, Richard L. Huganir, Jeffrey D. Rothstein, Donald L. Price, Philip C. Wong, Lee J. Martin, J. Julius Zhu, Huaibin Cai

研究成果: Article同行評審

66 引文 斯高帕斯(Scopus)

摘要

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.

原文English
頁(從 - 到)11798-11806
頁數9
期刊Journal of Neuroscience
26
發行號45
DOIs
出版狀態Published - 2006 11月 8

All Science Journal Classification (ASJC) codes

  • 一般神經科學

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