Role of Caspase 1 in Neurologic Disease

Friedlander, Robert M.

doi:10.1001/archneur.57.9.1273

Cited by 32 publications

(20 citation statements)

References 27 publications

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“…Previous results suggesting that IL-1β does not affect ALS pathogenesis in G37R transgenic ALS mice might be due to the different aggregation and inflammatory properties of the SOD1 mutation (G93A vs. G37R) or to the different mouse strains used (congenic C57BL/6 vs. mixed background B10RIII × C57BL/6) (17). In our experiments, IL-1β deficiency slowed disease progression but did not affect disease onset, arguing for a non-cell-autonomous, microglia-mediated acceleration of neurodegeneration (25). IL-1 is a pleiotropic cytokine involved in the induction of inflammatory and neurotoxic molecules such as COX2, inducible NOS, NO, or IL-6, which are implicated in ALS (4,16,18,26).…”

Section: Discussionmentioning

confidence: 58%

Mutant superoxide dismutase 1-induced IL-1β accelerates ALS pathogenesis

Meissner

Molawi

Zychlinsky

2010

Proc. Natl. Acad. Sci. U.S.A.

273

226

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ALS is a fatal motor neuron disease of adult onset. Neuroinflammation contributes to ALS disease progression; however, the inflammatory trigger remains unclear. We report that ALS-linked mutant superoxide dismutase 1 (SOD1) activates caspase-1 and IL-1β in microglia. Cytoplasmic accumulation of mutant SOD1 was sensed by an ASC containing inflammasome and antagonized by autophagy, limiting caspase-1-mediated inflammation. Notably, mutant SOD1 induced IL-1β correlated with amyloid-like misfolding and was independent of dismutase activity. Deficiency in caspase-1 or IL-1β or treatment with recombinant IL-1 receptor antagonist (IL-1RA) extended the lifespan of G93A-SOD1 transgenic mice and attenuated inflammatory pathology. These findings identify microglial IL-1β as a causative event of neuroinflammation and suggest IL-1 as a potential therapeutic target in ALS.A LS is a fatal neurodegenerative disorder characterized by progressive loss of motor neurons causing paralysis and finally death within 1-5 years after diagnosis. Dominant gain of function mutations of SOD1 are the most common genetic cause of ALS and also lead to motor neuron disease in mutant SOD1 transgenic mice (1). Mutations induce toxic misfolding and aggregation of SOD1 and interfere with cellular homeostasis in neurons and glia cells (2, 3). Neurodegeneration in ALS is accompanied by glia mediated neuroinflammation, which accelerates disease progression non-cell-autonomously (2, 4). One of the inflammatory markers found in the CNS of ALS mice is active caspase-1, which is also implicated in amyloid-β-mediated inflammation (5-7). Caspase-1 is activated in response to danger signals by cytosolic protein complexes called inflammasomes and proteolytically matures IL-1β and IL-18 (8). Accordingly, IL-1β levels are elevated in the CNS of mutant SOD1 transgenic mice and ALS patients (7). Extracellular mutant SOD1 has been shown to induce an inflammatory reaction by microglia (9, 10); however, the underlying mechanisms are poorly understood. ResultsMutant SOD1 Activates Caspase-1 in Microglia. To test whether mutant SOD1 can act as a danger signal that activates caspase-1 in resident microglia, we stimulated these cells with purified WT or mutant G93A-SOD1. G93A-SOD1, but not the WT protein, activated caspase-1 in microglia and macrophages in a dose-dependent manner ( Fig. 1 A and B). Consistently, time-and dose-dependent secretion of mature IL-1β was observed specifically upon G93A-SOD1 stimulation of microglia or macrophages (Figs. 1C and S1). G93A-SOD1 induced IL-1β maturation was dependent on caspase-1 and could not be observed in astrocytes (Fig. 1 D and E). Notably, caspase-1-mediated IL-1β release in response to G93A-SOD1 was independent of nonproteinaceous contaminants, LPS priming or transgenic mutant SOD1 expression in microglia or macrophages (Figs. S2 and S3). The inflammasome adaptor protein apoptosisassociated speck-like protein containing a caspase recruitment domain (ASC) was essential for IL-1β release in response to G93A-SOD1, whereas the ...

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Section: Discussionmentioning

confidence: 58%

Mutant superoxide dismutase 1-induced IL-1β accelerates ALS pathogenesis

Meissner

Molawi

Zychlinsky

2010

Proc. Natl. Acad. Sci. U.S.A.

273

226

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“…5 Zhu et al, 20 show a 2.5-fold increase of pro-Csp-1 in AD medial temporal tissues compared to controls and Csp-1 mRNA is increased in AD. 21 The most recognized function of Csp-1 is the conversion of pro-interleukin-1b (IL-1b) into mature IL-1b thereby eliciting an inflammatory response (reviewed by Friedlander 22 ). IL-1b is increased in AD but mostly associated with microglial activation suggesting a role for Csp-1 in inflammation.…”

Section: Discussionmentioning

confidence: 99%

Caspase-1 activation of caspase-6 in human apoptotic neurons

et al. 2005

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Active caspase-6 (Csp-6) induces cell death in primary cultures of human neurons and is abundant in the neuropathological lesions of Alzheimer's disease. However, the mode of Csp-6 activation is not known. Here, we show that the Csp-1 inhibitor, Z-YVAD-fmk specifically prevents activation of Csp-6 and cell death in human neurons. A transient increase in Csp-1-like activity and an increase in the p23Csp-1 subunit occur early after serum deprivation. Recombinant active Csp-1 (R-Csp-1) cleaves recombinant and neuronal pro-Csp-6 in vitro resulting in Csp-6 activity. However, R-Csp-1 does not induce cell death when microinjected in human neurons despite the inhibition of serum-deprivation induced cell death with a Csp-1 dominant negative construct. These results show that Csp-1 is an upstream positive regulator of Csp-6-mediated cell death in primary human neurons. Furthermore, these results suggest that the activation of Csp-1 must be accompanied by an apoptotic insult to induce Csp-6-mediated cell death.

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“…Some reports have shown that activation of cas-1 is involved in the induction of fibroblast apoptosis, and cas-1 activation also seemed to be related to apoptosis in several neurodegenerative diseases and subsequent ischemic events (41,42). Cas-1 has also been shown to activate cas-3 as well as cas-6 (43).…”

Section: Discussionmentioning

confidence: 99%

Caspase Activation in Retinas of Diabetic and Galactosemic Mice and Diabetic Patients

et al. 2002

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Apoptosis of retinal capillary cells begins early in diabetes and likely contributes to the capillary obliteration that is an important feature of diabetic retinopathy. Caspases are proteolytic enzymes that are closely involved in the induction and execution phases of apoptosis, but their role in the development of diabetic retinopathy has not been studied previously. Our study focused on the measurement of activities of multiple caspases in retinas of mice at different durations of diabetes. Several caspases (including caspases-1, -2, -6, -8, and -9) were activated as early as 2 months of diabetes. The caspases activity pattern changed with increasing duration of disease, suggesting a slowly developing caspases cascade. Activities of executioner caspases (e.g., cas-6 and -3) became elevated after longer duration of diabetes, and the induction of cas-3 activity was associated with the duration of diabetes at which capillary cells begin to show evidence of undergoing apoptosis. Retinas from patients with type 2 diabetes likewise showed a significant increase in activities of cas-1, -3, -4, and -6. For comparison, retinal caspases were also measured in experimental galactosemia, another model that develops a diabetic-like retinopathy. The pattern of caspases activation differed between diabetes and galactosemia, but cas-1 activity became elevated soon after elevation of blood hexose concentration in both. Caspases offer new therapeutic targets to test the role of apoptosis in the development of diabetic retinopathy.

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Role of Caspase 1 in Neurologic Disease

Cited by 32 publications

References 27 publications

Mutant superoxide dismutase 1-induced IL-1β accelerates ALS pathogenesis

Mutant superoxide dismutase 1-induced IL-1β accelerates ALS pathogenesis

Caspase-1 activation of caspase-6 in human apoptotic neurons

Caspase Activation in Retinas of Diabetic and Galactosemic Mice and Diabetic Patients

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