Neuronal loss and brain atrophy in mice lacking cathepsins B and L

Felbor, Ute; Kessler, Benedikt M.; Mothes, Walther; Goebel, Hans H.; Ploegh, Hidde L.; Bronson, Roderick T.; Olsen, Bjørn R.

doi:10.1073/pnas.112632299

Cited by 303 publications

(230 citation statements)

References 41 publications

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“…The importance of cathepsins including cathepsin B, D and L in autophagy has been demonstrated in animal models in which cathepsin deficiency leads to accumulation of autophagosomes in neuronal tissues. 38,39 In this study, we showed that zVAD is capable of inhibiting cathepsin B activity, being consistent with an earlier report that zVAD was able to suppress cathepsin activity in Jurkat cells. 30 In this regard, it is possible that, in addition to caspase inhibition and induction of endogenous ROS, which have been reported to be critical for cell death in L929 cells, 20,23 zVAD is also capable of inhibiting autophagy via its direct inhibitory effect on cathepsins as well as calpains; and the blockage of pro-survival autophagy then eventually also contributes to zVAD-induced necrotic cell death.…”

Section: Discussionsupporting

confidence: 79%

Autophagy plays a protective role during zVAD-induced necrotic cell death

Tan²,

Huang³

et al. 2008

Autophagy

159

135

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The aim of this study is to examine the role of autophagy in cell death by using a well-established system in which zVAD, a pan-caspase inhibitor, induces necrotic cell death in L929 murine fibrosarcoma cells. First, we observed the presence of autophagic hallmarks, including an increased number of autophagosomes and the accumulation of LC3-II in zVAD-treated L929 cells. Since the presence of such autophagic hallmarks could be the result of either increased flux of autophagy or blockage of autophagosome maturation (lysosomal fusion and degradation), we next tested the effect of rapamycin, a specific inhibitor for mTOR, and chloroquine, a lysosomal enzyme inhibitor, on zVAD-induced cell death. To our surprise, rapamycin, known to be an autophagy inducer, blocked zVAD-induced cell death, whereas chloroquine greatly sensitized zVAD-induced cell death in L929 cells. Moreover, similar results with rapamycin and chloroquine were also observed in U937 cells when challenged with zVAD. Consistently, induction of autophagy by serum starvation offered significant protection against zVADinduced cell death, whereas knockdown of Atg5, Atg7 or Beclin 1 markedly sensitized zVAD-induced cell death in L929 cells. More importantly, Atg genes knockdown completely abolished the protective effect of serum starvation on zVAD-induced cell death. Finally, we demonstrated that zVAD was able to inhibit lysosomal enzyme cathepsin B activity, and subsequently blocked autophagosome maturation. Taken together, in contrast to the previous conception that zVAD induces autophagic cell death, here we provide compelling evidence suggesting that autophagy serves as a cell survival mechanism and suppression of autophagy via inhibition of lysosomal function contributes to zVAD-induced necrotic cell death.

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Section: Discussionsupporting

confidence: 79%

Autophagy plays a protective role during zVAD-induced necrotic cell death

Tan²,

Huang³

et al. 2008

Autophagy

159

135

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“…27 Cathepsin L production has been attributed to neurons, microglia, astrocytes, fibroblasts from various origins, and other cell types. [28][29][30] These experiments confirm that cysteine protease activity generated acutely during focal ischemia in the striatum is predominantly cathepsin L, not cathepsin B, which responds much later ( Figure 1). 2 LG3 fragment from purified perlecan was significantly greater by activities secreted from microglia subject to OGD (filled bars) than by normoxia (open bars) (n = 6 per condition pooled from three independent experiments; P = 0.0043).…”

Section: Discussionsupporting

confidence: 62%

Cathepsin L Acutely Alters Microvessel Integrity within the Neurovascular Unit during Focal Cerebral Ischemia

Kanazawa

Hung

et al. 2015

J Cereb Blood Flow Metab

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During focal cerebral ischemia, the degradation of microvessel basal lamina matrix occurs acutely and is associated with edema formation and microhemorrhage. These events have been attributed to matrix metalloproteinases (MMPs). However, both known protease generation and ligand specificities suggest other participants. Using cerebral tissues from a non-human primate focal ischemia model and primary murine brain endothelial cells, astrocytes, and microglia in culture, the effects of active cathepsin L have been defined. Within 2 hours of ischemia onset cathepsin L, but not cathepsin B, activity appears in the ischemic core, around microvessels, within regions of neuron injury and cathepsin L expression. In in vitro studies, cathepsin L activity is generated during experimental ischemia in microglia, but not astrocytes or endothelial cells. In the acidic ischemic core, cathepsin L release is significantly increased with time. A novel ex vivo assay showed that cathepsin L released from microglia during ischemia degrades microvessel matrix, and interacts with MMP activity. Hence, the loss of microvessel matrix during ischemia is explained by microglial cathepsin L release in the acidic core during injury evolution. The roles of cathepsin L and its interactions with specific MMP activities during ischemia are relevant to strategies to reduce microvessel injury and hemorrhage.

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“…The combined deficiency of CB and CL results in early-onset neurodegeneration in mice that is reminiscent of neuronal ceroid lipofuscinoses (a hereditary neurodegenerative disease in humans), and cathepsin B À/À /L À/À mice exhibit a major degree of cerebral atrophy (Felbor et al, 2002). This atrophy is due to the massive apoptosis of selected neurons in the cerebral cortex and in the cerebellar Purkinje and granule cell layers.…”

Section: Lmp During Development and Aging Or Other Diseasesmentioning

confidence: 99%

Lysosomal membrane permeabilization in cell death

2008

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Mitochondrial outer membrane permeabilization (MOMP) constitutes one of the major checkpoint(s) of apoptotic and necrotic cell death. Recently, the permeabilization of yet another organelle, the lysosome, has been shown to initiate a cell death pathway, in specific circumstances. Lysosomal membrane permeabilization (LMP) causes the release of cathepsins and other hydrolases from the lysosomal lumen to the cytosol. LMP is induced by a plethora of distinct stimuli including reactive oxygen species, lysosomotropic compounds with detergent activity, as well as some endogenous cell death effectors such as Bax. LMP is a potentially lethal event because the ectopic presence of lysosomal proteases in the cytosol causes digestion of vital proteins and the activation of additional hydrolases including caspases. This latter process is usually mediated indirectly, through a cascade in which LMP causes the proteolytic activation of Bid (which is cleaved by the two lysosomal cathepsins B and D), which then induces MOMP, resulting in cytochrome c release and apoptosome-dependent caspase activation. However, massive LMP often results in cell death without caspase activation; this cell death may adopt a subapoptotic or necrotic appearance. The regulation of LMP is perturbed in cancer cells, suggesting that specific strategies for LMP induction might lead to novel therapeutic avenues.

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Neuronal loss and brain atrophy in mice lacking cathepsins B and L

Cited by 303 publications

References 41 publications

Autophagy plays a protective role during zVAD-induced necrotic cell death

Autophagy plays a protective role during zVAD-induced necrotic cell death

Cathepsin L Acutely Alters Microvessel Integrity within the Neurovascular Unit during Focal Cerebral Ischemia

Lysosomal membrane permeabilization in cell death

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