Protective mechanisms by cystatin C in neurodegenerative diseases

Gauthier, Sébastien A.; Kaur, Gurjinder; Mi, Weiqian; Tizon, Belen; Levy, Efrat

doi:10.2741/s170

Cited by 71 publications

(50 citation statements)

References 167 publications

(192 reference statements)

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“…40, 41 A similar paradigm for autophagic protein activation by cystatin C acting as a protective effector has been detailed by Tizon et al 32 This report demonstrated that the observed increase in the number of autophagosomes after exposure to cystatin C reflects induction of a fully functional autophagy via the mTOR pathway that includes competent proteolytic clearance of autophagy substrates by lysosomes. Recent in vitro and in vivo data have demonstrated that cystatin C plays protective roles via pathways that are dependent on inhibition of cysteine proteases, such as cathepsin B, or by induction of autophagy 42 and protects neuronal cells against mutant copper-zinc superoxide dismutase-mediated toxicity. 43 Our data suggest that the increase in CST1 expression in response to AF treatment induces autophagy as a chemotherapy-resistant mechanism.…”

Section: Discussionmentioning

confidence: 99%

Cystatin SN inhibits auranofin-induced cell death by autophagic induction and ROS regulation via glutathione reductase activity in colorectal cancer

Lee

Cho

et al. 2017

Cell Death Dis

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Cystatin SN (CST1) is a specific inhibitor belonging to the cystatin superfamily that controls the proteolytic activities of cysteine proteases such as cathepsins. Our previous study showed that high CST1 expression enhances tumor metastasis and invasiveness in colorectal cancer. Recently, auranofin (AF), a gold(I)-containing thioredoxin reductase 1 (TrxR1) inhibitor, has been used clinically to treat rheumatoid arthritis. AF is a proteasome-associated deubiquitinase inhibitor and can act as an anti-tumor agent. In this study, we investigated whether CST1 expression induces autophagy and tumor cell survival. We also investigated the therapeutic effects of AF as an anti-tumor agent in colorectal cancer (CRC) cells. We found that CRC cells expressing high levels of CST1 undergo increased autophagy and exhibit chemotherapeutic resistance to AF-induced cell death, while those expressing low levels of CST1 are sensitive to AF. We also observed that knockdown of CST1 in high-CST1 CRC cells using CST1-specific small interfering RNAs attenuated autophagic activation and restored AF-induced cell mortality. Conversely, the overexpression of CST1 increased autophagy and viability in cells expressing low levels of CST1. Interestingly, high expression of CST1 attenuates AF-induced cell death by inhibiting intracellular reactive oxygen species (ROS) generation, as demonstrated by the fact that the blockage of ROS production reversed AF-induced cell death in CRC cells. In addition, upregulation of CST1 expression increased cellular glutathione reductase (GR) activity, reducing the cellular redox state and inducing autophagy in AF-treated CRC cells. These results suggest that high CST1 expression may be involved in autophagic induction and protects from AF-induced cell death by inhibition of ROS generation through the regulation of GR activity.

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Section: Discussionmentioning

confidence: 99%

Cystatin SN inhibits auranofin-induced cell death by autophagic induction and ROS regulation via glutathione reductase activity in colorectal cancer

Lee

Cho

et al. 2017

Cell Death Dis

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“…CysC plays a variety of biological roles, ranging from regulating normal tissue processes such as cell proliferation and growth (Sun, 1989; Tavera et al, 1992), astrocyte differentiation (Kumada et al, 2004) and bone resorption (Lerner and Grubb, 1992) to modulating potentially pathogenic events, including infection (Bobek and Levine, 1992; van Kasteren et al, 2011), inflammatory responses (Bobek and Levine, 1992; Warfel et al, 1987), tumor metastasis (Huh et al, 1999; Taupin et al, 2000), and neurodegenerative disorders [reviewed in (Gauthier et al, 2011; Tizon and Levy, 2006)]. The relationship CysC expression appears to have to normal as well as pathological processes supports the idea that the levels of CysC in specific tissues and body fluids may serve as a marker for a variety of diseases, for disease progression, and for the effect of therapy.…”

Section: Cysc In Diseasementioning

confidence: 99%

“…CysC has been suggested to play a role in nervous system repair following injury and disease [reviewed in (Gauthier et al, 2011; Tizon and Levy, 2006)], and CysC CSF levels in the normal brain are five times higher than they are in serum, consistent with an important physiological role for CysC in the brain (Grubb, 1992). Multiple investigators have documented alterations in CysC levels in the CSF in neurodegenerative diseases (Maetzler et al, 2010; Mares et al, 2009; Mori et al, 2009; Pasinetti et al, 2006; Tsuji-Akimoto et al, 2009; Yang et al, 2009).…”

Section: Cysc In Diseasementioning

confidence: 99%

“…Changes in brain CysC levels have also been observed in diverse animal models of neurodegenerative conditions including those caused by facial nerve axotomy (Miyake et al, 1996), noxious input to the sensory spinal cord (Yang et al, 2001), perforant path transections (Ying et al, 2002), hypophysectomy (Katakai et al, 1997), transient forebrain ischemia (Ishimaru et al, 1996; Palm et al, 1995), photothrombotic stroke (Pirttila and Pitkanen, 2006), and induction of epilepsy (Aronica et al, 2001; Hendriksen et al, 2001; Lukasiuk et al, 2002). While these findings argue that CysC levels in the CSF and the brain are broadly responsive to brain injury, CysC appears to also be a sensitive marker of ongoing neuronal injury and one that shows progressive disruption during disease pathology (Gauthier et al, 2011; Wilson et al).…”

Section: Cysc In Diseasementioning

confidence: 99%

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Cystatin C in aging and in Alzheimer’s disease

Mathews

Levy

2016

Ageing Research Reviews

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Under normal conditions, the function of catalytically active proteases is regulated, in part, by their endogenous inhibitors, and any change in the synthesis and/or function of a protease or its endogenous inhibitors may result in inappropriate protease activity. Altered proteolysis as a result of an imbalance between active proteases and their endogenous inhibitors can occur during normal aging, and such changes have also been associated with multiple neuronal diseases, including Amyotrophic Lateral Sclerosis (ALS), rare heritable neurodegenerative disorders, ischemia, some forms of epilepsy, and Alzheimer’s disease (AD). One of the most extensively studied endogenous inhibitor is the cysteine-protease inhibitor cystatin C (CysC). Changes in the expression and secretion of CysC in the brain have been described in various neurological disorders and in animal models of neurodegeneration, underscoring a role for CysC in these conditions. In the brain, multiple in vitro and in vivo findings have demonstrated that CysC plays protective roles via pathways that depend upon the inhibition of endosomal-lysosomal pathway cysteine proteases, such as cathepsin B (Cat B), via the induction of cellular autophagy, via the induction of cell proliferation, or via the inhibition of amyloid-β (Aβ) aggregation. We review the data demonstrating the protective roles of CysC under conditions of neuronal challenge and the protective pathways induced by CysC under various conditions. Beyond highlighting the essential role that balanced proteolytic activity plays in supporting normal brain aging, these findings suggest that CysC is a therapeutic candidate that can potentially prevent brain damage and neurodegeneration.

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“…The balance between the harming and the protective mechanisms will ultimately determine the fate of the injured brain [3]. For instance, cathepsins are lysosomal cystein-proteases that appear to be released after traumatic injury and increase neuronal death; on the other hand, the release of cystatin C (CC), an endogenous inhibitor of cathepsins B, H, K, L, and S, appears to be a self-protective brain response [4]. …”

Section: Introductionmentioning

confidence: 99%

Cystatin C Has a Dual Role in Post-Traumatic Brain Injury Recovery

Martínez-Vargas

Soto-Nuñez

Tabla-Ramon

et al. 2014

IJMS

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Cathepsin B is one of the major lysosomal cysteine proteases involved in neuronal protein catabolism. This cathepsin is released after traumatic injury and increases neuronal death; however, release of cystatin C, a cathepsin inhibitor, appears to be a self-protective brain response. Here we describe the effect of cystatin C intracerebroventricular administration in rats prior to inducing a traumatic brain injury. We observed that cystatin C injection caused a dual response in post-traumatic brain injury recovery: higher doses (350 fmoles) increased bleeding and mortality, whereas lower doses (3.5 to 35 fmoles) decreased bleeding, neuronal damage and mortality. We also analyzed the expression of cathepsin B and cystatin C in the brains of control rats and of rats after a traumatic brain injury. Cathepsin B was detected in the brain stem, cerebellum, hippocampus and cerebral cortex of control rats. Cystatin C was localized to the choroid plexus, brain stem and cerebellum of control rats. Twenty-four hours after traumatic brain injury, we observed changes in both the expression and localization of both proteins in the cerebral cortex, hippocampus and brain stem. An early increase and intralysosomal expression of cystatin C after brain injury was associated with reduced neuronal damage.

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Protective mechanisms by cystatin C in neurodegenerative diseases

Cited by 71 publications

References 167 publications

Cystatin SN inhibits auranofin-induced cell death by autophagic induction and ROS regulation via glutathione reductase activity in colorectal cancer

Cystatin SN inhibits auranofin-induced cell death by autophagic induction and ROS regulation via glutathione reductase activity in colorectal cancer

Cystatin C in aging and in Alzheimer’s disease

Cystatin C Has a Dual Role in Post-Traumatic Brain Injury Recovery

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