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The Journal of Neuroscience, November 8, 2006, 26(45):11798-11806; doi:10.1523/JNEUROSCI.2084-06.2006

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Neurobiology of Disease
Amyotrophic Lateral Sclerosis 2-Deficiency Leads to Neuronal Degeneration in Amyotrophic Lateral Sclerosis through Altered AMPA Receptor Trafficking

Chen Lai,¹ Chengsong Xie,¹ Stefanie G. McCormack,² Hsueh-Cheng Chiang,³ Marta K. Michalak,^2,7 Xian Lin,¹ Jayanth Chandran,¹ Hoon Shim,¹ Mika Shimoji,¹ Mark R. Cookson,¹ Richard L. Huganir,^4,6 Jeffrey D. Rothstein,⁵ Donald L. Price,^3,4,5 Philip C. Wong,^3,4 Lee J. Martin,^3,4 J. Julius Zhu,² and Huaibin Cai¹

¹Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, ²Department of Pharmacology and Neuroscience Graduate Program, University of Virginia School of Medicine, Charlottesville, Virginia 22908, ³Departments of Pathology, ⁴Neuroscience, and ⁵Neurology, and ⁶Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and ⁷Biotechnology Graduate Program, Technical University of ód, 90-924 ód, Poland

Correspondence should be addressed to Dr. Huaibin Cai, Section of Transgenesis, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35, Room 1A116, 35 Convent Drive, Bethesda, MD 20892-3707. Email: caih{at}mail.nih.gov

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.

Key words: ALS2; knock-out mouse; motor neuron; GRIP1; AMPA receptor; excitotoxicity

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Received May 16, 2006; revised Aug. 31, 2006; accepted Oct. 4, 2006.

Correspondence should be addressed to Dr. Huaibin Cai, Section of Transgenesis, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35, Room 1A116, 35 Convent Drive, Bethesda, MD 20892-3707. Email: caih{at}mail.nih.gov

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