Abstract
Cystatin C (CysC) expression in the brain is elevated in human patients with epilepsy, in animal models of neurodegenerative conditions, and in response to injury, but whether up-regulated CysC expression is a manifestation of neurodegeneration or a cellular repair response is not understood. This study demonstrates that human CysC is neuroprotective in cultures exposed to cytotoxic challenges, including nutritional-deprivation, colchicine, staurosporine, and oxidative stress. While CysC is a cysteine protease inhibitor, cathepsin B inhibition was not required for the neuroprotective action of CysC. Cells responded to CysC by inducing fully functional autophagy via the mTOR pathway, leading to enhanced proteolytic clearance of autophagy substrates by lysosomes. Neuroprotective effects of CysC were prevented by inhibiting autophagy with beclin 1 siRNA or 3-methyladenine. Our findings show that CysC plays a protective role under conditions of neuronal challenge by inducing autophagy via mTOR inhibition and are consistent with CysC being neuroprotective in neurodegenerative diseases. Thus, modulation of CysC expression has therapeutic implications for stroke, Alzheimer's disease, and other neurodegenerative disorders.
Highlights
Cystatin C (CysC) [1] is considered an important endogenous inhibitor of cysteine protease activity because of its potent in vitro inhibition of cathepsins B, H, K, L and S and its presence in all mammalian body fluids and tissues
Primary cortical neurons isolated from brains of CysC overexpressing transgenic mice [4] are more protected from death, and cells isolated from CysC knockout mice [5] are more sensitive to in vitro toxicity compared to cells isolated from brains of wild type mice
We demonstrate that CysC induces autophagy in cells under basal conditions, and enhances the autophagic activation in cells exposed to nutritional deprivation and oxidative stress
Summary
CysC [1] is considered an important endogenous inhibitor of cysteine protease activity because of its potent in vitro inhibition of cathepsins B, H, K, L and S and its presence in all mammalian body fluids and tissues (for review [2]). It has a broad spectrum of biological roles in numerous cellular systems, with growthpromoting activity, inflammation down-regulating function, and anti-viral and anti-bacterial properties (for review [3]). In vitro studies using various cell types exposed to a variety of toxic stimuli have reached conflicting conclusions as to whether CysC is protective or toxic to the cells (for review [3])
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