Functional Role of Caspase-1 and Caspase-3 in an ALS Transgenic Mouse Model

Li, Mingwei; Ona, Victor; Guégan, Christelle; Chen, Minghua; Jackson‐Lewis, Vernice; Andrews, L. John; Olszewski, Adam J.; Stieg, Philip E.; Lee, Jean-Pyo.; Przedborski, Serge; Friedlander, Robert M.

doi:10.1126/science.288.5464.335

Cited by 662 publications

(482 citation statements)

References 27 publications

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“…In contrast to grip strength measurements, the rotarod also measures other aspects of function such as balance and endurance and has been used to detect therapyderived functional improvements in a number of animal models of neuromuscular disease. 11,23 Irrespective of the functional measurements, additional outcome measures that evaluate the specific effects on muscle (e.g., histological, bioenergetic, and enzymatic) are necessary to adequately preclinically screen potential therapies.…”

Section: Discussionmentioning

confidence: 99%

Nutritional therapy improves function and complements corticosteroid intervention in mdx mice

et al. 2005

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Corticosteroid therapy for Duchenne muscular dystrophy is effective but associated with long-term side effects. To determine the potential therapeutic benefit from four nutritional compounds (creatine monohydrate, conjugated linoleic acid, ␣-lipoic acid, and ␤-hydroxy-␤-methylbutyrate) alone, in combination, and with corticosteroids (prednisolone), we evaluated the effects on several variables in exercising mdx mice. Outcome measures included grip strength, rotarod performance, serum creatine kinase levels, muscle metabolites, internalized myonuclei, and retroperitoneal fat pad weight. In isolation, each nutritional treatment showed some benefit, with the combination therapy showing the most consistent benefits. Prednisolone and the combination therapy together provided the most consistent evidence of efficacy; increased peak grip strength (P Ͻ 0.05), decreased grip strength fatigue (P Ͻ 0.05), decreased number of internalized myonuclei (P Ͻ 0.01), and smaller retroperitoneal fat pad stores (P Ͻ 0.001). This study provided evidence for therapeutic benefit from a four-compound combination therapy alone, and in conjunction with corticosteroids in the mdx model of DMD.

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Section: Discussionmentioning

confidence: 99%

Nutritional therapy improves function and complements corticosteroid intervention in mdx mice

et al. 2005

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“…Already at 30 hpf, and coincident with changes in cell morphology, perp morphant embryos display severely increased numbers of AO-positive cells in the skin and notochord (Figure 8a, e, g), whereas embryos injected with the perp 4 mm control MO show normal numbers (Figure 8c, f, g). In perp morphants, the number of AO-positive cells can be significantly reduced by treating the embryos with the pan-caspase inhibitor zVADfmk, 43 indicative for caspase-dependent apoptosis (Figure 8b, g). Consistently, perp morphant embryos display a dramatic increase in the number of FITC-VAD-fmk-positive cells (Figure 8h), whereas only few these cells were detected in embryos injected with perp 4 mm MO (Figure 8i).…”

Section: Loss Of Perp Function Leads To Enhanced Apoptosis Rates In Tmentioning

confidence: 99%

“…To block caspase activity and thereby caspase-dependent apoptosis, zebrafish embryos were treated with the membrane-permeable pancaspase inhibitor zVAD-fmk (carbobenzoxy-valyl-alanyl-aspartyl-[Omethyl]-fluoromethylketone, Promega, Madison, WI, USA), 43 as described elsewhere. 73 In situ hybridization, immunohistochemistry, and cell death detection Whole-mount in situ hybridizations and immunohistochemistry were carried out as previously described.…”

Section: Inhibition Of Caspase Activitymentioning

confidence: 99%

Perp is required for tissue-specific cell survival during zebrafish development

2004

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The tumor suppressor p53 has two alternative effects, causing either cell cycle arrest or apoptosis. These different effects are supposed to be mediated by the transcriptional activation of different target genes. perp, encoding a transmembrane protein of the Pmp22 family, is a transcriptional p53 target exclusively upregulated in apoptotic cells. However, its role during normal development had remained largely unclear. Here, we report the isolation and characterization of a zebrafish perp homolog. Upon overexpression in early zebrafish embryos, perp induces apoptosis. In addition, it contributes to p53-dependent and UVinduced cell death. However, during normal zebrafish development, perp displays a p53-independent and spatially restricted expression in specific cell types and tissues. Antisensemediated loss of Perp function leads to increased apoptosis in perp-expressing cells of the developing skin and notochord. We conclude that, in contrast to its proapoptotic function in stressed cells, Perp plays an antiapoptotic role during normal zebrafish development to regulate tissue-specific cell survival. Cell Death and Differentiation (2005) Keywords: perp; p53; pmp22; apoptosis; cell survival; zebrafish; development Abbreviations: AO, acridine orange; BrdU, 5 0 Bromo-2 0 -desoxyuridine; DNp63, amino-terminally truncated isoform of p63; EST, expressed sequence tag; EVL, enveloping layer; hpf, hours postfertilization; mdm2, mouse double minute 2; MO, morpholino oligonucleotide; RT-PCR, polymerase chain reaction after reverse transcription of RNA; SDS-PAGE, sodiumdodecylsulfate polyacrylamide gel electrophoresis; TAp73, transactivating N-terminally full-length isoform of p73; TUNEL, terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling; UV, ultraviolet; 4 mm, four mismatch control

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“…24 -32 Although cell death during ALS is believed to be apoptotic in nature, this is an area of active research and debate. [42][43][44][45][46][47][48][49][50][51] Evidence from studies on nonneuronal cells suggests that E2F-1-induced cell death is via apoptosis and can be either p53-dependent or p53-independent. 52,53 However a role for E2F-1 or other cell-cycle proteins in neurodegeneration during ALS is unknown.…”

mentioning

confidence: 99%

Alterations in G1 to S Phase Cell-Cycle Regulators during Amyotrophic Lateral Sclerosis

Ranganathan

Bowser

2003

The American Journal of Pathology

151

111

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Amyotrophic lateral sclerosis (ALS) is characterizedby progressive degeneration of the motor neurons in the cerebral cortex, brain stem, and spinal cord. However, the mechanisms that regulate the initiation and/or progression of motor neuron loss in this disease remain enigmatic. Cell-cycle proteins and transcriptional regulators such as cyclins, cyclin-associated kinases, the retinoblastoma gene product (pRb), and E2F-1 function during cellular proliferation, differentiation, and cell death pathways. Recent data has implicated increased expression and activation of various cell-cycle proteins in neuronal cell death. We have examined the expression and subcellular distribution of G 1 to S phase cell-cycle regulators in the spinal cord, motor cortex, and sensory cortex from clinically and neuropathologically diagnosed sporadic ALS cases and age-matched controls. Our results indicate hyperphosphorylation of the retinoblastoma protein in motor neurons during ALS, concurrent with increased levels of cyclin D, and redistribution of E2F-1 into the cytoplasm of motor neurons and glia. These data suggest that G 1 to S phase activation occurs during ALS and may participate in molecular mechanisms regulating motor neuron death. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease exemplified by neuronal loss in the motor cortex, brainstem, and spinal cord ventral horn. This progressive neurodegeneration results in muscle atrophy, paralysis, and death. Disease onset may occur at any age but is most common between 40 to 70 years of age. The average time interval from diagnosis to mortality is ϳ4 years. 1,2 Familial ALS comprises a fraction (5 to 10%) of ALS cases and is predominantly inherited in an autosomal dominant manner and includes mutations in the SOD1 and the ALS2 genes. [3][4][5][6][7] The etiology of ALS is thought to be multifactorial. Factors believed to participate in motor neuron degeneration include glutamate-mediated excitotoxicity, free radical accumulation because of oxidative stress, increased intracellular calcium, mitochondrial dysfunction, cytoskeletal abnormalities, astrogliosis, and genetic mutations. 8 -13 Neuronal dysfunction because of retrograde degeneration of the presynaptic axons may occur as the result of insufficient release of activity-dependent target-derived neurotrophic factors. 14 One important consequence of inappropriate trophic factor support is altered intracellular signaling to the nucleus. Signaling from the cell surface to the nucleus modulates chromatin structure and the activity of transcription factors, resulting in altered gene transcription. One potential mechanism leading to neuronal death in ALS includes altered expression of pro-and anti-apoptotic genes. 15 Another potential cell death mechanism is the inappropriate expression or activation of cell-cycle proteins. 16 The cell cycle is associated with the phasespecific expression or modification of defined sets of cell-cycle regulatory genes that regulate cellular proliferation, differentiation or entry into...

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Functional Role of Caspase-1 and Caspase-3 in an ALS Transgenic Mouse Model

Cited by 662 publications

References 27 publications

Nutritional therapy improves function and complements corticosteroid intervention in mdx mice

Nutritional therapy improves function and complements corticosteroid intervention in mdx mice

Perp is required for tissue-specific cell survival during zebrafish development

Alterations in G1 to S Phase Cell-Cycle Regulators during Amyotrophic Lateral Sclerosis

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