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ARTICLE, Cellular/Molecular

Delaying Caspase Activation by Bcl-2: A Clue to Disease Retardation in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Slobodanka Vukosavic, Leonidas Stefanis, Vernice Jackson-Lewis, Christelle Guégan, Norma Romero, Caiping Chen, Michel Dubois-Dauphin and Serge Przedborski
Journal of Neuroscience 15 December 2000, 20 (24) 9119-9125; DOI: https://doi.org/10.1523/JNEUROSCI.20-24-09119.2000
Slobodanka Vukosavic
1Departments of Neurology and
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Leonidas Stefanis
1Departments of Neurology and
2Pathology, Columbia University, New York, New York 10032, and
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Vernice Jackson-Lewis
1Departments of Neurology and
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Christelle Guégan
1Departments of Neurology and
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Norma Romero
1Departments of Neurology and
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Caiping Chen
1Departments of Neurology and
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Michel Dubois-Dauphin
3Department of Psychiatry, HUG Belle-Idee, University of Geneva School of Medicine, 1225 Geneva, Switzerland
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Serge Przedborski
1Departments of Neurology and
2Pathology, Columbia University, New York, New York 10032, and
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    Fig. 1.

    Caspase-1 and caspase-3 mRNA levels are altered in the spinal cords of transgenic mSOD1 mice. A, B, Trend toward increased levels of caspase-1 mRNA in transgenic mSOD1 mice at the beginning of symptoms and at end-stage. A, C, Significant increased caspase-3 mRNA levels in transgenic mSOD1 mice at the beginning of symptoms and at end-stage; *p < 0.05 higher than age-matched nontransgenic controls, Newman–Keulspost hoc test. N, Nontransgenic;A, asymptomatic; O, onset of symptoms;E, end-stage.

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    Fig. 2.

    Activation of caspase-1 and caspase-3 in the spinal cords of transgenic mSOD1 mice. A, B, By 12 weeks of age the levels of pro-caspase-1 (45 kDa; black bars) decrease, whereas those of its cleaved fragment (20 kDa; white bars) increase in transgenic mSOD1 mice. A, C, A few weeks later the same phenomenon occurs for pro-caspase-3 (32 kDa;black bars) and its cleaved fragment (17 kDa;white bars); *p < 0.05 and †p < 0.01 different from age-matched nontransgenic controls, Newman–Keuls post hoc test.N, Nontransgenic; A, asymptomatic (at 4, 6, 8, 12 weeks of age); O, onset of symptoms;E, end-stage; C, cerebellum.

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    Fig. 3.

    Increased caspase-1- and caspase-3-like activities in the spinal cords of transgenic mSOD1 mice. Caspase-1-like activity (black bars) increases before caspase-3-like activity (white bars), but both peak at the beginning of symptoms. Data are mean ± SEM for 5–15 mice per group; *p < 0.05 and **p < 0.01 higher than age-matched nontransgenic controls, Newman–Keulspost hoc test. N, Nontransgenic;A, asymptomatic (at 4, 6, 8, 12 weeks of age);O, onset of symptoms; E, end-stage;C, cerebellum.

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    Fig. 4.

    In nontransgenic controls a large number of cells from the lumbar segment are strongly immunoreactive for pro-caspase-1 (A) and pro-caspase-3 (D); those cells have a neuronal morphology (see higher magnification inB and E). In end-stage transgenic mSOD1, there is a dramatic loss of pro-caspase-1-positive (C) and pro-caspase-3-positive (F) neurons in the lumbar segment. Conversely, specific immunostaining for CM1 (G; seearrow) and fractin (H; seearrow) is seen only in symptomatic transgenic mSOD1 mice within apoptotic cells (see insets;arrowheads indicate apoptotic chromatin clumps) and colocalizes with the neuronal marker neurofilament (I), but not with the glial marker GFAP (J). Scale bars: A, C, D, F–H, 100 μm; B, E, I, J, 20 μm.

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    Fig. 5.

    Bcl-2 delays caspase activation. Western blot analyses (A–D) show that transgenic mSOD1/Bcl-2 mice that are aged-matched (AM) with end-stage (E) transgenic mSOD1 exhibit significantly lower levels of cleaved caspase-1 (A, C) and caspase-3 (B, D) than end-stage transgenic mSOD1. However, end-stage transgenic mSOD1/Bcl-2 mice exhibit levels of cleaved caspase-1 (A, C) and caspase-3 (B, D) comparable with end-stage transgenic mSOD1. A similar situation is found for the activity of caspase-1 and caspase-3 (E); *p < 0.05 higher and †p < 0.05 lower than end-stage transgenic mSOD1 and mSOD1/Bcl-2 mice, Newman–Keuls post hoc test.

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    Table 1.

    Spinal cord cells containing activated caspase-3 and β-actin fragment

    mSOD1NontransgenicmSOD1/Bcl-2
    Beginning of symptomsEnd-stageAge-matched1-aAge-matched1-aEnd-stage
    MN65  ± 3*32  ± 21-16074  ± 261  ± 2*34  ± 21-160
    CM1 × 103.3  ± 0.62.7  ± 0.601.2  ± 0.5†3.1  ± 0.9
    Fractin × 103.7  ± 0.62.8  ± 0.801.5  ± 0.4†2.7  ± 0.5
    • ↵F1-a Killed simultaneously with transgenic mSOD1 end-stage littermates. Cells were counted in the lumbar segment of the spinal cord. Data represent mean per section ± SEM for three to five mice per group. MN, Motor neuron.

    • ↵* p < 0.05 and

    • ↵F1-160 p< 0.01 lower than wild-type mice;

    • ↵† p < 0.05 lower than beginning of symptoms and end-stage transgenicmSOD1, Newman–Keuls post hoc test.

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The Journal of Neuroscience: 20 (24)
Journal of Neuroscience
Vol. 20, Issue 24
15 Dec 2000
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Delaying Caspase Activation by Bcl-2: A Clue to Disease Retardation in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis
Slobodanka Vukosavic, Leonidas Stefanis, Vernice Jackson-Lewis, Christelle Guégan, Norma Romero, Caiping Chen, Michel Dubois-Dauphin, Serge Przedborski
Journal of Neuroscience 15 December 2000, 20 (24) 9119-9125; DOI: 10.1523/JNEUROSCI.20-24-09119.2000

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Delaying Caspase Activation by Bcl-2: A Clue to Disease Retardation in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis
Slobodanka Vukosavic, Leonidas Stefanis, Vernice Jackson-Lewis, Christelle Guégan, Norma Romero, Caiping Chen, Michel Dubois-Dauphin, Serge Przedborski
Journal of Neuroscience 15 December 2000, 20 (24) 9119-9125; DOI: 10.1523/JNEUROSCI.20-24-09119.2000
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Keywords

  • amyotrophic lateral sclerosis
  • apoptosis
  • Bcl-2
  • caspase
  • superoxide dismutase
  • neuronal death

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