Induction of autophagy by cystatin C: A mechanism that protects murine primary cortical neurons and neuronal cell lines

Belen Tizon, Susmita Sahoo, Haung Yu, Sebastien Gauthier, Asok R. Kumar, Panaiyur Mohan, Matthew Figliola, Monika Pawlik, Anders Grubb, Yasuo Uchiyama, Urmi Bandyopadhyay, Ana Maria Cuervo, Ralph A. Nixon, Efrat Levy

Research output: Contribution to journalArticle

82 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere9819
JournalPLoS One
Volume5
Issue number3
DOIs
StatePublished - 2010

Fingerprint

Cystatin C
cystatins
autophagy
Autophagy
Neurons
neurons
Cells
cell lines
Cell Line
mice
neuroprotective effect
neurodegenerative diseases
Neurodegenerative Diseases
Neurodegenerative diseases
Cysteine Proteinase Inhibitors
cysteine proteinase inhibitors
cathepsin B
Cathepsin B
Oxidative stress
Staurosporine

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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.

In: PLoS One, Vol. 5, No. 3, e9819, 2010.

Research output: Contribution to journalArticle

Tizon, B, Sahoo, S, Yu, H, Gauthier, S, Kumar, AR, Mohan, P, Figliola, M, Pawlik, M, Grubb, A, Uchiyama, Y, Bandyopadhyay, U, Cuervo, AM, Nixon, RA & Levy, E 2010, 'Induction of autophagy by cystatin C: A mechanism that protects murine primary cortical neurons and neuronal cell lines', PLoS One, vol. 5, no. 3, e9819. https://doi.org/10.1371/journal.pone.0009819
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. In: PLoS One. 2010 ; Vol. 5, No. 3.
@article{5a428049377544aa98c19637e2a8ed55,
title = "Induction of autophagy by cystatin C: A mechanism that protects murine primary cortical neurons and neuronal cell lines",
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.",
author = "Belen Tizon and Susmita Sahoo and Haung Yu and Sebastien Gauthier and Kumar, {Asok R.} and Panaiyur Mohan and Matthew Figliola and Monika Pawlik and Anders Grubb and Yasuo Uchiyama and Urmi Bandyopadhyay and Cuervo, {Ana Maria} and Nixon, {Ralph A.} and Efrat Levy",
year = "2010",
doi = "10.1371/journal.pone.0009819",
language = "English (US)",
volume = "5",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "3",

}

TY - JOUR

T1 - Induction of autophagy by cystatin C

T2 - A mechanism that protects murine primary cortical neurons and neuronal cell lines

AU - Tizon, Belen

AU - Sahoo, Susmita

AU - Yu, Haung

AU - Gauthier, Sebastien

AU - Kumar, Asok R.

AU - Mohan, Panaiyur

AU - Figliola, Matthew

AU - Pawlik, Monika

AU - Grubb, Anders

AU - Uchiyama, Yasuo

AU - Bandyopadhyay, Urmi

AU - Cuervo, Ana Maria

AU - Nixon, Ralph A.

AU - Levy, Efrat

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77956475769&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77956475769&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0009819

DO - 10.1371/journal.pone.0009819

M3 - Article

C2 - 20352108

AN - SCOPUS:77956475769

VL - 5

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 3

M1 - e9819

ER -