Protease Inhibitors and their Involvement in Neurological Disorders

Tizon, Belen; Levy, Efrat

doi:10.1007/978-0-387-30379-6_20

Cited by 11 publications

(13 citation statements)

References 447 publications

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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%

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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Section: Cysc In Diseasementioning

confidence: 99%

Cystatin C in aging and in Alzheimer’s disease

Mathews

Levy

2016

Ageing Research Reviews

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“…92 Specific polymorphisms of cystatin C, an inhibitor of cysteine proteases that is neuroprotective in injury settings, is associated with reduced AD risk. 93 Aging, a sine qua non for AD development, is accompanied by slowed degradation of long-lived proteins 94 reflecting declines in macroautophagic proteolysis and chaperone-mediated autophagy. 95 Lipofuscin accumulation, a hallmark phenomenon of cellular aging that was previously thought to be innocuous, interferes with the fusion of lysosomes with autophagosomes.…”

Section: Lysosomal System Function Is Disrupted By Factors Causing Ormentioning

confidence: 99%

Neurodegenerative lysosomal disorders: A continuum from development to late age

Nixon

Yang²,

Lee³

2008

Autophagy

328

267

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Neuronal survival requires continuous lysosomal turnover of cellular constituents delivered by autophagy and endocytosis. Primary lysosomal dysfunction in inherited congenital "lysosomal storage" disorders is well known to cause severe neurodegenerative phenotypes associated with accumulations of lysosomes and autophagic vacuoles (AVs). Recently, the number of inherited adult-onset neurodegenerative diseases caused by proteins that regulate protein sorting and degradation within the endocytic and autophagic pathways has grown considerably. In this Perspective, we classify a group of neurodegenerative diseases across the lifespan as disorders of lysosomal function, which feature extensive autophagic-endocytic-lysosomal neuropathology and may share mechanisms of neurodegeneration related to degradative failure and lysosomal destabilization. We highlight Alzheimer's disease as a disease within this group and discuss how each of the genes and other risk factors promoting this disease contribute to progressive lysosomal dysfunction and neuronal cell death.

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“…7 Cystatin C (CysC), a secreted cysteine protease inhibitor belonging to the type 2 family of cystatins, is found in all mammalian body fluids and tissues. Both CysB and CysC inhibit cathepsins (Cat) B, H, L, S, and K. 8 -10 Uncontrolled proteolysis as a result of imbalance between active proteases and their endogenous inhibitors has been associated with diverse diseases such as Alzheimer's disease, cancer, rheumatoid arthritis, multiple sclerosis, muscular dystrophy, liver disorders, lysosomal disorders, and diabetes (reviewed in Tizon and Levy 11 ). Furthermore, precursor forms of lysosomal enzymes, which are not susceptible to inhibition by endogenous inhibitors, have leaked from the lysosomes in many diseases.…”

mentioning

confidence: 99%

Cystatin C Rescues Degenerating Neurons in a Cystatin B-Knockout Mouse Model of Progressive Myoclonus Epilepsy

Kaur

Mohan

Pawlik

et al. 2010

The American Journal of Pathology

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In vitro studies have shown that cystatin C (CysC) is neuroprotective. Here we demonstrate that CysC is neuroprotective in vivo, in a mouse model of the inherited neurodegenerative disorder, progressive myoclonic epilepsy type 1 (EPM1). Loss-of-function mutations in the cystatin B (CysB) gene, an intracellular cysteine protease inhibitor, lead to this human disease. A CysB-knockout (CysBKO) mouse model develops symptoms that mimic EPM1. CysB deficiency in these mice results in enhanced cathepsin B and D activities, indicating lysosomal dysfunction. We show that expression of CysC is enhanced in the brains of CysBKO mice. Crossbreeding of CysBKO mice with either CysC-overexpressing transgenic mice or CysCknockout mice demonstrates that clinical symptoms and neuropathologies, including motor coordination disorder, cerebellar atrophy, neuronal loss in the cerebellum and cerebral cortex, and gliosis caused by CysB deficiency, are rescued by CysC overexpression and exacerbated by CysC deficiency. Thus, CysC effectively rescues the CysB loss-of-function mutations, facilitating the reversal of pathophysiological changes and suggesting a novel therapeutic intervention for patients with EPM1 and other neurodegenerative disorders.

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Protease Inhibitors and their Involvement in Neurological Disorders

Cited by 11 publications

References 447 publications

Cystatin C in aging and in Alzheimer’s disease

Cystatin C in aging and in Alzheimer’s disease

Neurodegenerative lysosomal disorders: A continuum from development to late age

Cystatin C Rescues Degenerating Neurons in a Cystatin B-Knockout Mouse Model of Progressive Myoclonus Epilepsy

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