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, HsuehCheng Chinag, 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

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Abstract

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.

Original languageEnglish
Pages (from-to)11798-11806
Number of pages9
JournalJournal of Neuroscience
Volume26
Issue number45
DOIs
Publication statusPublished - 2006 Nov 8

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AMPA Receptors
Amyotrophic Lateral Sclerosis
Glutamate Receptors
Receptor-Interacting Protein Serine-Threonine Kinases
Motor Neurons
Neurons
Nerve Degeneration
Motor Neuron Disease
Juvenile Amyotrophic Lateral Sclerosis 2
Calcium

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Lai, Chen ; Xie, Chengsong ; McCormack, Stefanie G. ; Chinag, HsuehCheng ; 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. / Amyotrophic lateral sclerosis 2-deficiency leads to neuronal degeneration in amyotrophic lateral sclerosis through altered AMPA receptor trafficking. In: Journal of Neuroscience. 2006 ; Vol. 26, No. 45. pp. 11798-11806.
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title = "Amyotrophic lateral sclerosis 2-deficiency leads to neuronal degeneration in amyotrophic lateral sclerosis through altered AMPA receptor trafficking",
abstract = "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.",
author = "Chen Lai and Chengsong Xie and McCormack, {Stefanie G.} and HsuehCheng Chinag and Michalak, {Marta K.} and Xian Lin and Jayanth Chandran and Hoon Shim and Mika Shimoji and Cookson, {Mark R.} and Huganir, {Richard L.} and Rothstein, {Jeffrey D.} and Price, {Donald L.} and Wong, {Philip C.} and Martin, {Lee J.} and Zhu, {J. Julius} and Huaibin Cai",
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Lai, C, Xie, C, McCormack, SG, Chinag, H, Michalak, MK, Lin, X, Chandran, J, Shim, H, Shimoji, M, Cookson, MR, Huganir, RL, Rothstein, JD, Price, DL, Wong, PC, Martin, LJ, Zhu, JJ & Cai, H 2006, 'Amyotrophic lateral sclerosis 2-deficiency leads to neuronal degeneration in amyotrophic lateral sclerosis through altered AMPA receptor trafficking', Journal of Neuroscience, vol. 26, no. 45, pp. 11798-11806. https://doi.org/10.1523/JNEUROSCI.2084-06.2006

Amyotrophic lateral sclerosis 2-deficiency leads to neuronal degeneration in amyotrophic lateral sclerosis through altered AMPA receptor trafficking. / Lai, Chen; Xie, Chengsong; McCormack, Stefanie G.; Chinag, HsuehCheng; 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.

In: Journal of Neuroscience, Vol. 26, No. 45, 08.11.2006, p. 11798-11806.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Amyotrophic lateral sclerosis 2-deficiency leads to neuronal degeneration in amyotrophic lateral sclerosis through altered AMPA receptor trafficking

AU - Lai, Chen

AU - Xie, Chengsong

AU - McCormack, Stefanie G.

AU - Chinag, HsuehCheng

AU - Michalak, Marta K.

AU - Lin, Xian

AU - Chandran, Jayanth

AU - Shim, Hoon

AU - Shimoji, Mika

AU - Cookson, Mark R.

AU - Huganir, Richard L.

AU - Rothstein, Jeffrey D.

AU - Price, Donald L.

AU - Wong, Philip C.

AU - Martin, Lee J.

AU - Zhu, J. Julius

AU - Cai, Huaibin

PY - 2006/11/8

Y1 - 2006/11/8

N2 - 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.

AB - 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.

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