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Induction of Autophagy by Cystatin C: A Mechanism That Protects Murine Primary Cortical Neurons and Neuronal Cell Lines

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 s...

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Autores principales: Tizon, Belen, Sahoo, Susmita, Yu, Haung, Gauthier, Sebastien, Kumar, Asok R., Mohan, Panaiyur, Figliola, Matthew, Pawlik, Monika, Grubb, Anders, Uchiyama, Yasuo, Bandyopadhyay, Urmi, Cuervo, Ana Maria, Nixon, Ralph A., Levy, Efrat
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2843718/
https://www.ncbi.nlm.nih.gov/pubmed/20352108
http://dx.doi.org/10.1371/journal.pone.0009819
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author Tizon, Belen
Sahoo, Susmita
Yu, Haung
Gauthier, Sebastien
Kumar, Asok R.
Mohan, Panaiyur
Figliola, Matthew
Pawlik, Monika
Grubb, Anders
Uchiyama, Yasuo
Bandyopadhyay, Urmi
Cuervo, Ana Maria
Nixon, Ralph A.
Levy, Efrat
author_facet Tizon, Belen
Sahoo, Susmita
Yu, Haung
Gauthier, Sebastien
Kumar, Asok R.
Mohan, Panaiyur
Figliola, Matthew
Pawlik, Monika
Grubb, Anders
Uchiyama, Yasuo
Bandyopadhyay, Urmi
Cuervo, Ana Maria
Nixon, Ralph A.
Levy, Efrat
author_sort Tizon, Belen
collection PubMed
description 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.
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spelling pubmed-28437182010-03-27 Induction of Autophagy by Cystatin C: A Mechanism That Protects Murine Primary Cortical Neurons and Neuronal Cell Lines Tizon, Belen Sahoo, Susmita Yu, Haung Gauthier, Sebastien Kumar, Asok R. Mohan, Panaiyur Figliola, Matthew Pawlik, Monika Grubb, Anders Uchiyama, Yasuo Bandyopadhyay, Urmi Cuervo, Ana Maria Nixon, Ralph A. Levy, Efrat PLoS One Research Article 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. Public Library of Science 2010-03-23 /pmc/articles/PMC2843718/ /pubmed/20352108 http://dx.doi.org/10.1371/journal.pone.0009819 Text en Tizon et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Tizon, Belen
Sahoo, Susmita
Yu, Haung
Gauthier, Sebastien
Kumar, Asok R.
Mohan, Panaiyur
Figliola, Matthew
Pawlik, Monika
Grubb, Anders
Uchiyama, Yasuo
Bandyopadhyay, Urmi
Cuervo, Ana Maria
Nixon, Ralph A.
Levy, Efrat
Induction of Autophagy by Cystatin C: A Mechanism That Protects Murine Primary Cortical Neurons and Neuronal Cell Lines
title Induction of Autophagy by Cystatin C: A Mechanism That Protects Murine Primary Cortical Neurons and Neuronal Cell Lines
title_full Induction of Autophagy by Cystatin C: A Mechanism That Protects Murine Primary Cortical Neurons and Neuronal Cell Lines
title_fullStr Induction of Autophagy by Cystatin C: A Mechanism That Protects Murine Primary Cortical Neurons and Neuronal Cell Lines
title_full_unstemmed Induction of Autophagy by Cystatin C: A Mechanism That Protects Murine Primary Cortical Neurons and Neuronal Cell Lines
title_short Induction of Autophagy by Cystatin C: A Mechanism That Protects Murine Primary Cortical Neurons and Neuronal Cell Lines
title_sort induction of autophagy by cystatin c: a mechanism that protects murine primary cortical neurons and neuronal cell lines
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2843718/
https://www.ncbi.nlm.nih.gov/pubmed/20352108
http://dx.doi.org/10.1371/journal.pone.0009819
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