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Proteolytic fragments of laminin promote excitotoxic neurodegeneration by up-regulation of the KA1 subunit of the kainate receptor.

Chen ZL, Yu H, Yu WM, Pawlak R, Strickland S - J. Cell Biol. (2008)

Bottom Line: Degradation of the extracellular matrix (ECM) protein laminin contributes to excitotoxic cell death in the hippocampus, but the mechanism of this effect is unknown.Interfering with KA1 function with a specific anti-KA1 antibody protected against KA-induced neuronal death both in vitro and in vivo.These results demonstrate a novel pathway for neurodegeneration involving proteolysis of the ECM and KA1 KA receptor subunit up-regulation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065, USA.

ABSTRACT
Degradation of the extracellular matrix (ECM) protein laminin contributes to excitotoxic cell death in the hippocampus, but the mechanism of this effect is unknown. To study this process, we disrupted laminin gamma1 (lamgamma1) expression in the hippocampus. Lamgamma1 knockout (KO) and control mice had similar basal expression of kainate (KA) receptors, but the lamgamma1 KO mice were resistant to KA-induced neuronal death. After KA injection, KA1 subunit levels increased in control mice but were unchanged in lamgamma1 KO mice. KA1 levels in tissue plasminogen activator (tPA)-KO mice were also unchanged after KA, indicating that both tPA and laminin were necessary for KA1 up-regulation after KA injection. Infusion of plasmin-digested laminin-1 into the hippocampus of lamgamma1 or tPA KO mice restored KA1 up-regulation and KA-induced neuronal degeneration. Interfering with KA1 function with a specific anti-KA1 antibody protected against KA-induced neuronal death both in vitro and in vivo. These results demonstrate a novel pathway for neurodegeneration involving proteolysis of the ECM and KA1 KA receptor subunit up-regulation.

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Activation of intracellular death signaling pathways was impaired in lamγ1 KO mice. (A–C) The phosphorylation levels of MKK4 (A), JNK (B), and c-Jun (C) were significantly less in the hippocampus of lamγ1 KO mice compared with those of control (Con) mice 2 h after KA injection. Quantitative analyses are shown as bar graphs directly below the respective Western blots (n = 7 per genotype; signal intensities were normalized to actin). Error bars indicate SEM.
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fig3: Activation of intracellular death signaling pathways was impaired in lamγ1 KO mice. (A–C) The phosphorylation levels of MKK4 (A), JNK (B), and c-Jun (C) were significantly less in the hippocampus of lamγ1 KO mice compared with those of control (Con) mice 2 h after KA injection. Quantitative analyses are shown as bar graphs directly below the respective Western blots (n = 7 per genotype; signal intensities were normalized to actin). Error bars indicate SEM.

Mentions: c-fos was not induced in the CA1 region of lamγ1 KO mice after KA injection, indicating that the excitotoxic resistance phenotype could be caused by a failure of intracellular death signaling pathway activation. The JNK intracellular signaling pathway plays an important role in mediating excitotoxic neuronal cell death (Yang et al., 1997; Saporito et al., 1998; Behrens et al., 1999; Wu et al., 2000; Savinainen et al., 2001; Borsello et al., 2003; Kuan et al., 2003; Zhang et al., 2006). Therefore, we tested whether activation of the JNK signaling pathway was affected in lamγ1 KO mice. Because JNK can be activated by MAPK kinase 4 (MKK4; Cuenda, 2000), we analyzed MKK4 phosphorylation levels in control and lamγ1 KO mice after KA injection. Phosphorylation of MKK4 was dramatically reduced in lamγ1 KO mice compared with control mice after KA injection (Fig. 3 A). Phosphorylated JNK was detected in control but not in lamγ1 KO mice (Fig. 3 B).


Proteolytic fragments of laminin promote excitotoxic neurodegeneration by up-regulation of the KA1 subunit of the kainate receptor.

Chen ZL, Yu H, Yu WM, Pawlak R, Strickland S - J. Cell Biol. (2008)

Activation of intracellular death signaling pathways was impaired in lamγ1 KO mice. (A–C) The phosphorylation levels of MKK4 (A), JNK (B), and c-Jun (C) were significantly less in the hippocampus of lamγ1 KO mice compared with those of control (Con) mice 2 h after KA injection. Quantitative analyses are shown as bar graphs directly below the respective Western blots (n = 7 per genotype; signal intensities were normalized to actin). Error bars indicate SEM.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2606967&req=5

fig3: Activation of intracellular death signaling pathways was impaired in lamγ1 KO mice. (A–C) The phosphorylation levels of MKK4 (A), JNK (B), and c-Jun (C) were significantly less in the hippocampus of lamγ1 KO mice compared with those of control (Con) mice 2 h after KA injection. Quantitative analyses are shown as bar graphs directly below the respective Western blots (n = 7 per genotype; signal intensities were normalized to actin). Error bars indicate SEM.
Mentions: c-fos was not induced in the CA1 region of lamγ1 KO mice after KA injection, indicating that the excitotoxic resistance phenotype could be caused by a failure of intracellular death signaling pathway activation. The JNK intracellular signaling pathway plays an important role in mediating excitotoxic neuronal cell death (Yang et al., 1997; Saporito et al., 1998; Behrens et al., 1999; Wu et al., 2000; Savinainen et al., 2001; Borsello et al., 2003; Kuan et al., 2003; Zhang et al., 2006). Therefore, we tested whether activation of the JNK signaling pathway was affected in lamγ1 KO mice. Because JNK can be activated by MAPK kinase 4 (MKK4; Cuenda, 2000), we analyzed MKK4 phosphorylation levels in control and lamγ1 KO mice after KA injection. Phosphorylation of MKK4 was dramatically reduced in lamγ1 KO mice compared with control mice after KA injection (Fig. 3 A). Phosphorylated JNK was detected in control but not in lamγ1 KO mice (Fig. 3 B).

Bottom Line: Degradation of the extracellular matrix (ECM) protein laminin contributes to excitotoxic cell death in the hippocampus, but the mechanism of this effect is unknown.Interfering with KA1 function with a specific anti-KA1 antibody protected against KA-induced neuronal death both in vitro and in vivo.These results demonstrate a novel pathway for neurodegeneration involving proteolysis of the ECM and KA1 KA receptor subunit up-regulation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065, USA.

ABSTRACT
Degradation of the extracellular matrix (ECM) protein laminin contributes to excitotoxic cell death in the hippocampus, but the mechanism of this effect is unknown. To study this process, we disrupted laminin gamma1 (lamgamma1) expression in the hippocampus. Lamgamma1 knockout (KO) and control mice had similar basal expression of kainate (KA) receptors, but the lamgamma1 KO mice were resistant to KA-induced neuronal death. After KA injection, KA1 subunit levels increased in control mice but were unchanged in lamgamma1 KO mice. KA1 levels in tissue plasminogen activator (tPA)-KO mice were also unchanged after KA, indicating that both tPA and laminin were necessary for KA1 up-regulation after KA injection. Infusion of plasmin-digested laminin-1 into the hippocampus of lamgamma1 or tPA KO mice restored KA1 up-regulation and KA-induced neuronal degeneration. Interfering with KA1 function with a specific anti-KA1 antibody protected against KA-induced neuronal death both in vitro and in vivo. These results demonstrate a novel pathway for neurodegeneration involving proteolysis of the ECM and KA1 KA receptor subunit up-regulation.

Show MeSH
Related in: MedlinePlus