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

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.

Pubmed ID: 17093100 RIS Download

Mesh terms: Adaptor Proteins, Signal Transducing | Amyotrophic Lateral Sclerosis | Animals | Biotinylation | Cell Line | Cell Membrane | Cell Survival | Cerebral Cortex | Disease Models, Animal | Excitatory Amino Acid Agonists | Guanine Nucleotide Exchange Factors | Humans | Immunoprecipitation | In Vitro Techniques | Mice | Mice, Knockout | Nerve Degeneration | Nerve Tissue Proteins | Neurons | Protein Transport | Receptors, AMPA | Spinal Cord | Subcellular Fractions | Transfection | alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid

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Associated grants

  • Agency: NINDS NIH HHS, Id: R01 NS052098
  • Agency: NINDS NIH HHS, Id: NS053570
  • Agency: NINDS NIH HHS, Id: NS34100
  • Agency: NINDS NIH HHS, Id: R01 NS034100
  • Agency: NINDS NIH HHS, Id: NS40014
  • Agency: NINDS NIH HHS, Id: NS52098
  • Agency: NINDS NIH HHS, Id: R01 NS040014
  • Agency: Intramural NIH HHS, Id: Z99 AG999999
  • Agency: Intramural NIH HHS, Id: Z01 AG000959-04
  • Agency: NINDS NIH HHS, Id: R01 NS053570

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