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Mediated Activation of Caspase-1 and Caspase-3 in a Mouse Model of Amyotrophic Lateral Sclerosis

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Mediated Activation of Caspase-1 and Caspase-3 in a Mouse Model of Amyotrophic Lateral Sclerosis The Journal of Neuroscience, July 2, 2003 • 23(13):5455–5460 • 5455 Brief Communication Dissociation between Neurodegeneration and Caspase-11- Mediated Activation of Caspase-1 and Caspase-3 in a Mouse Model of Amyotrophic Lateral Sclerosis Shin Jung Kang, Ivelisse Sanchez, Naisen Jing, and Junying Yuan Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 Caspase-11 is a key regulator of caspase-1 and caspase-3 activation under pathological conditions. We show here that the expression of caspase-11 is upregulated in the spinal cord of superoxide dismutase 1 (SOD1) G93A transgenic mice, a mouse model of amyotrophic lateral sclerosis (ALS), before the onset of motor dysfunction and remains at the high levels throughout the course of disease. The caspase-1-andcaspase-3-likeactivities,aswellasthelevelofinterleukin-1␤,weresignificantlyreducedinthespinalcordofsymptomatic caspase-11Ϫ/Ϫ;SOD1 G93A mice compared with that of caspase-11ϩ/Ϫ; SOD1 G93A mice. However, neurodegeneration, inflammatory responses, and the disease onset and progression in SOD1 G93A transgenic mice were not altered by the ablation ofcaspase-11 gene. Thus, although caspases may contribute to certain aspects of pathology in this mouse model of ALS, their inhibition is not sufficient to prevent neurodegeneration. Our study urges caution when considering the inhibition of caspases as a direct therapeutic method for the treatment of chronic neurodegenerative diseases. Key words: ALS; motor neuron degeneration; neurodegeneration; SOD1; caspase; apoptosis Introduction mouse model at end stage of the disease has been also reported Amyotrophic lateral sclerosis (ALS) is a fatal neurological disor- (Gue´gan et al., 2001, 2002). Moreover, inhibition of caspase(s) der characterized by selective degeneration of upper and lower with peptide inhibitors or by introducing a dominant-negative motor neurons, leading to paralysis and death at ϳ1–5 years after mutant of caspase-1 delayed the onset and progression of the the onset (Cleveland and Rothstein, 2001). The disease has both disease symptoms in G93A SOD1 (G93A) transgenic mice sporadic and familial forms, with the latter accounting for ϳ5% (Friedlander et al., 1997; Li et al., 2000), suggesting the impor- of the cases. In 1993, Rosen et al. demonstrated that several mu- tance of caspase-mediated apoptosis in the ALS pathology. tations in the Cu 2ϩ/Zn 2ϩ superoxide dismutase (SOD1) are The possible involvement of both caspase-1 and caspase-3 in causally responsible for a subset of familial ALS (FALS). Consis- the pathogenesis of ALS strongly suggested the involvement of tent with a causal role of SOD1 mutations in FALS, transgenic caspase-11 in this process because caspase-11 is a key upstream mice expressing human SOD1 mutants develop age-dependent regulator of both caspase-1 and -3 under pathological conditions progressive motor neuron degeneration with cellular pathologi- (Wang et al., 1998; Kang et al., 2000, 2002). Caspase-11Ϫ/Ϫ mice cal features similar to that of human ALS. are defective in interleukin-1␤ (IL-1␤) maturation and resistant Recent studies suggested caspase-mediated apoptosis as a pos- to lipopolysaccharide (LPS)-induced septic shock (Wang et al., sible mechanism for motor neuron degeneration in ALS (Fried- 1998). Apoptosis and caspase-3 activation by LPS shock or isch- lander et al., 1997; Kostic et al., 1997; Li et al., 2000). Caspases are emic brain injury are also defective in caspase-11Ϫ/Ϫ mice (Kang actively regulated cysteine proteases responsible for the signal et al., 2000, 2002). Thus, caspase-11 serves as an initiator caspase transduction and execution of apoptosis (Cryns and Yuan, 1998). in apoptosis under these pathological conditions. Activation of caspase-1 and caspase-3 in the spinal cords of mu- Although there have been reports of caspase activation and of tant SOD1 mice and ALS patients has been reported previously beneficial effect of general caspase inhibition in mouse models of (Martin, 1999; Li et al., 2000; Pasinelli et al., 2000; Vukosavic et ALS, a critical role of individual caspases in mutant SOD1- al., 2000). More recently, activation of caspase-7, -8, and -9 in a mediated neurodegeneration has not been examined in different caspase mutant mice. Therefore, it remains to be resolved whether the activation of caspases and the resulting apoptosis Received Feb. 14, 2003; revised April 24, 2003; accepted April 24, 2003. This work was supported by grants from the National Institute on Aging and the Amyotrophic Lateral Sclerosis play an indispensable role in mediating neurodegeneration in Association(J.Y.).WethankChristianMahlkefortechnicalassistanceinmousegenotyping,HongZhuforgenerating ALS. Furthermore, the contribution of caspase-mediated toxicity monoclonal antibodies, and the Yuan laboratory members for helpful advice. in relation to the early events of pathogenesis in mutant SOD1 Correspondence should be addressed to Junying Yuan, Department of Cell Biology, Harvard Medical School, 240 transgenic mice, such as mitochondrial dilation, neurofilament Longwood Avenue, Boston, MA 02115. E-mail: [email protected] abnormality, and glutamate transporter downregulation in as- I. Sanchez’s present address: Department of Anatomy and Neurobiology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118. trocytes, remains unclear. Copyright © 2003 Society for Neuroscience 0270-6474/03/235455-06$15.00/0 In the present study, we provide evidence that caspase-11 5456 • J. Neurosci., July 2, 2003 • 23(13):5455–5460 Kang et al. • Caspase-11 in a Mouse Model of ALS plays a critical role in caspase-1 and -3 activation during patho- genesis of G93A mice, a mouse model of FALS (Gurney et al., 1994). However, deletion of caspase-11 was found to have no effect on the disease onset, progression, or inflammatory re- sponse in this model of FALS. Our results bring into the question the proposed causal role of these caspases in the pathogenesis– neurodegeneration in FALS. Materials and Methods Transgenic mice. Mouse lines expressing human SOD1 mutant G93A [C57BL/6J-TgN(SOD1-G93A)1Gurdl] were obtained from The Jackson Laboratory (Bar Harbor, ME). Caspase-11-deficient mice have been de- scribed previously (Wang et al., 1998). To minimize the variations in genetic background, one SOD1 G93A transgenic male mouse was mated with one female caspase-11Ϫ/Ϫ mouse to generate F1. An F1 male mouse (caspase-11ϩ/Ϫ;SOD1 G93A) was mated with two caspase-11Ϫ/Ϫ mice and one caspase-11ϩ/Ϫ mouse to generate all of the genotypes for com- parison. A total of five litters were used for clinical assessment. Mice were maintained in a pathogen-free environment, and experiments on mice were conducted according to the protocols approved by the Harvard Medical School Animal Care Committee. Clinical assessment. The phenotypes of the G93A mice were assessed daily for resting tremor and every other day for upper and lower limb weakness based on their ability to hold on to the cage bar for 20 sec as described previously (Gurney et al., 1994). Immunoblots. For immunoblotting, tissue samples were pulverized in liquid N2, and the resulting tissue powder was solubilized in 0.7 ml of radioimmunoprecipitation assay lysis buffer (150 mM NaCl, 1% Triton X-100, 0.1% SDS, and 1% sodium deoxycholate in 50 mM Tris-HCl, pH 7.4) with protease inhibitor mixtures (Boehringer Mannheim, Mann- heim, Germany). Tissue lysates were processed for immunoblot as de- scribed previously (Kang et al., 2000). Antibodies against human- and mouse-specific SOD1 were obtained from Chemicon (Temecula, CA). Caspase activity assay. Freshly isolated spinal cords were pulverized in the liquid nitrogen-chilled mortar. Caspase activity was determined us- ing methods described by Kang et al. (2000). Immunohistochemistry, terminal deoxynucleotidyl transferase-mediated Figure 1. Upregulation of caspase-11 at the disease onset in G93A mice and reduction of biotinylated UTP nick end labeling, and Nissl staining. Immunostaining of caspase-1andcaspase-3activationincaspase-11Ϫ/Ϫ;G93Adouble-mutantmice.A,Upregu- anti-MacI (macrophage antigen I) (Caltag, Burlingame, CA), anti-GFAP lation of caspase-11 and appearance of active caspase-1 and caspase-3 fragments in the G93A (glial fibrillary acidic protein), or anti-NeuN (neuronal-specific nuclear spinal cords. Two hundred micrograms of the spinal cord lysates of G93A mice at indicated days protein) (Chemicon, Temecula, CA) antibody and terminal deoxynu- of age were immunoprecipitated using monoclonal anti-caspase-11 antibody and blotted with cleotidyl transferase-mediated biotinylated UTP nick end labeling the same antibody for detection of the two caspase-11 full-length products of 43 and 38 kDa (TUNEL) assay were done using methods described by Kang et al. (2000). (C11FL). Control (CTL) lysates were prepared from a 140-d-old wild-type mouse. Eighty micro- Nissl staining was performed using cresyl violet following the standard grams of the samples were also immunoblotted with monoclonal anti-caspase-1 antibody for method. detection of full-length caspase-1 (C1FL) and the active form (active C1) and with anti-active caspase-3 antibody (active C3). *IgGH , IgG heavy chain; *nsp, nonspecific. Nonspecific bands Results serveasaloadingcontrol.B,ReductionofacDEVDase,acYVADase,andacVEHDaseactivityinthe Caspase-11 regulates caspase-1 and -3 activation in the spinal absence of caspase-11 in the caspase-11Ϫ/Ϫ; G93A spinal cords. At 120 d of age, thoracic (T) cords of G93A mice and lumbar (L) spinal
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