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.
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892-3707, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Lai
authors.forename: Chengsong
authors.initials: C
authors.lastname: Xie
authors.forename: Stefanie G
authors.initials: SG
authors.lastname: McCormack
authors.forename: Hsueh-Cheng
authors.initials: HC
authors.lastname: Chiang
authors.forename: Marta K
authors.initials: MK
authors.lastname: Michalak
authors.forename: Xian
authors.initials: X
authors.lastname: Lin
authors.forename: Jayanth
authors.initials: J
authors.lastname: Chandran
authors.forename: Hoon
authors.initials: H
authors.lastname: Shim
authors.forename: Mika
authors.initials: M
authors.lastname: Shimoji
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
authors.forename: Richard L
authors.initials: RL
authors.lastname: Huganir
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Rothstein
authors.forename: Donald L
authors.initials: DL
authors.lastname: Price
authors.forename: Philip C
authors.initials: PC
authors.lastname: Wong
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Martin
authors.forename: J Julius
authors.initials: JJ
authors.lastname: Zhu
authors.forename: Huaibin
authors.initials: H
authors.lastname: Cai
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications* / Q000378:metabolism*; D000818:Animals; D019921:Biotinylation / Q000379:methods; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000209:etiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects; D018091:Receptors, AMPA / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014162:Transfection / Q000379:methods; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C512358:Als2 protein, mouse; D018690:Excitatory Amino Acid Agonists; C491309:Grip1 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C104722:glutamate receptor ionotropic, AMPA 2