Reactive oxygen species trigger motoneuron death in non-cell-autonomous models of als through activation of c-Abl signaling

Fabiola Rojas, David Gonzalez, Nicole Cortes, Estibaliz Ampuero, Diego E. Hernández, Elsa Fritz, Sebastián Abarzua, Alexis Martinez, Alvaro A. Elorza, Alejandra Alvarez, Felipe Court, Brigitte Van Zundert

Resultado de la investigación: Article

29 Citas (Scopus)

Resumen

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which pathogenesis and death of motor neurons are triggered by non-cell-autonomous mechanisms. We showed earlier that exposing primary rat spinal cord cultures to conditioned media derived from primary mouse astrocyte conditioned media (ACM) that express human SOD1G93A(ACM-hSOD1G93A) quickly enhances Nav channel- mediated excitability and calcium influx, generates intracellular reactive oxygen species (ROS), and leads to death of motoneurons within days. Here we examined the role of mitochondrial structure and physiology and of the activation of c-Abl, a tyrosine kinase that induces apoptosis. We show that ACM-hSOD1G93A, but not ACM-hSOD1WT, increases c-Abl activity in motoneurons, interneurons and glial cells, starting at 60 min; the c-Abl inhibitor STI571 (imatinib) prevents this ACM-hSOD1G93A-mediated motoneuron death. Interestingly, similar results were obtained with ACM derived from astrocytes expressing SOD1G86Ror TDP43A315T. We further find that co-application of ACM-SOD1G93Awith blockers of Nav channels (spermidine, mexiletine, or riluzole) or anti-oxidants (Trolox, esculetin, or tiron) effectively prevent c-Abl activation and motoneuron death. In addition, ACM-SOD1G93Ainduces alterations in the morphology of neuronal mitochondria that are related with their membrane depolarization. Finally, we find that blocking the opening of the mitochondrial permeability transition pore with cyclosporine A, or inhibiting mitochondrial calcium uptake with Ru360, reduces ROS production and c-Abl activation. Together, our data point to a sequence of events in which a toxic factor(s) released by ALS-expressing astrocytes rapidly induces hyper-excitability, which in turn increases calcium influx and affects mitochondrial structure and physiology. ROS production, mediated at least in part through mitochondrial alterations, trigger c-Abl signaling and lead to motoneuron death.

Idioma originalEnglish
Número de artículoA203
Páginas (desde-hasta)1-20
Número de páginas20
PublicaciónFrontiers in Cellular Neuroscience
Volumen9
N.ºJune
DOI
EstadoPublished - 9 jun 2015

Huella dactilar

Motor Neurons
Astrocytes
Conditioned Culture Medium
Reactive Oxygen Species
Amyotrophic Lateral Sclerosis
Calcium
1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt
Riluzole
Mexiletine
Spermidine
Poisons
Interneurons
Oxidants
Neuroglia
Neurodegenerative Diseases
Protein-Tyrosine Kinases
Cyclosporine
Spinal Cord
Mitochondria
Apoptosis

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Citar esto

Rojas, Fabiola ; Gonzalez, David ; Cortes, Nicole ; Ampuero, Estibaliz ; Hernández, Diego E. ; Fritz, Elsa ; Abarzua, Sebastián ; Martinez, Alexis ; Elorza, Alvaro A. ; Alvarez, Alejandra ; Court, Felipe ; Van Zundert, Brigitte. / Reactive oxygen species trigger motoneuron death in non-cell-autonomous models of als through activation of c-Abl signaling. En: Frontiers in Cellular Neuroscience. 2015 ; Vol. 9, N.º June. pp. 1-20.
@article{8aa99ba68a7946de8bd51aa0496f5b11,
title = "Reactive oxygen species trigger motoneuron death in non-cell-autonomous models of als through activation of c-Abl signaling",
abstract = "Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which pathogenesis and death of motor neurons are triggered by non-cell-autonomous mechanisms. We showed earlier that exposing primary rat spinal cord cultures to conditioned media derived from primary mouse astrocyte conditioned media (ACM) that express human SOD1G93A(ACM-hSOD1G93A) quickly enhances Nav channel- mediated excitability and calcium influx, generates intracellular reactive oxygen species (ROS), and leads to death of motoneurons within days. Here we examined the role of mitochondrial structure and physiology and of the activation of c-Abl, a tyrosine kinase that induces apoptosis. We show that ACM-hSOD1G93A, but not ACM-hSOD1WT, increases c-Abl activity in motoneurons, interneurons and glial cells, starting at 60 min; the c-Abl inhibitor STI571 (imatinib) prevents this ACM-hSOD1G93A-mediated motoneuron death. Interestingly, similar results were obtained with ACM derived from astrocytes expressing SOD1G86Ror TDP43A315T. We further find that co-application of ACM-SOD1G93Awith blockers of Nav channels (spermidine, mexiletine, or riluzole) or anti-oxidants (Trolox, esculetin, or tiron) effectively prevent c-Abl activation and motoneuron death. In addition, ACM-SOD1G93Ainduces alterations in the morphology of neuronal mitochondria that are related with their membrane depolarization. Finally, we find that blocking the opening of the mitochondrial permeability transition pore with cyclosporine A, or inhibiting mitochondrial calcium uptake with Ru360, reduces ROS production and c-Abl activation. Together, our data point to a sequence of events in which a toxic factor(s) released by ALS-expressing astrocytes rapidly induces hyper-excitability, which in turn increases calcium influx and affects mitochondrial structure and physiology. ROS production, mediated at least in part through mitochondrial alterations, trigger c-Abl signaling and lead to motoneuron death.",
keywords = "ALS, C-Abl, Mitochondria, Motor neuron, Non-cell-autonomous, Reactive oxygen species (ROS)",
author = "Fabiola Rojas and David Gonzalez and Nicole Cortes and Estibaliz Ampuero and Hern{\'a}ndez, {Diego E.} and Elsa Fritz and Sebasti{\'a}n Abarzua and Alexis Martinez and Elorza, {Alvaro A.} and Alejandra Alvarez and Felipe Court and {Van Zundert}, Brigitte",
year = "2015",
month = "6",
day = "9",
doi = "10.3389/fncel.2015.00203",
language = "English",
volume = "9",
pages = "1--20",
journal = "Frontiers in Cellular Neuroscience",
issn = "1662-5102",
publisher = "Frontiers Media S.A.",
number = "June",

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Rojas, F, Gonzalez, D, Cortes, N, Ampuero, E, Hernández, DE, Fritz, E, Abarzua, S, Martinez, A, Elorza, AA, Alvarez, A, Court, F & Van Zundert, B 2015, 'Reactive oxygen species trigger motoneuron death in non-cell-autonomous models of als through activation of c-Abl signaling', Frontiers in Cellular Neuroscience, vol. 9, n.º June, A203, pp. 1-20. https://doi.org/10.3389/fncel.2015.00203

Reactive oxygen species trigger motoneuron death in non-cell-autonomous models of als through activation of c-Abl signaling. / Rojas, Fabiola; Gonzalez, David; Cortes, Nicole; Ampuero, Estibaliz; Hernández, Diego E.; Fritz, Elsa; Abarzua, Sebastián; Martinez, Alexis; Elorza, Alvaro A.; Alvarez, Alejandra; Court, Felipe; Van Zundert, Brigitte.

En: Frontiers in Cellular Neuroscience, Vol. 9, N.º June, A203, 09.06.2015, p. 1-20.

Resultado de la investigación: Article

TY - JOUR

T1 - Reactive oxygen species trigger motoneuron death in non-cell-autonomous models of als through activation of c-Abl signaling

AU - Rojas, Fabiola

AU - Gonzalez, David

AU - Cortes, Nicole

AU - Ampuero, Estibaliz

AU - Hernández, Diego E.

AU - Fritz, Elsa

AU - Abarzua, Sebastián

AU - Martinez, Alexis

AU - Elorza, Alvaro A.

AU - Alvarez, Alejandra

AU - Court, Felipe

AU - Van Zundert, Brigitte

PY - 2015/6/9

Y1 - 2015/6/9

N2 - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which pathogenesis and death of motor neurons are triggered by non-cell-autonomous mechanisms. We showed earlier that exposing primary rat spinal cord cultures to conditioned media derived from primary mouse astrocyte conditioned media (ACM) that express human SOD1G93A(ACM-hSOD1G93A) quickly enhances Nav channel- mediated excitability and calcium influx, generates intracellular reactive oxygen species (ROS), and leads to death of motoneurons within days. Here we examined the role of mitochondrial structure and physiology and of the activation of c-Abl, a tyrosine kinase that induces apoptosis. We show that ACM-hSOD1G93A, but not ACM-hSOD1WT, increases c-Abl activity in motoneurons, interneurons and glial cells, starting at 60 min; the c-Abl inhibitor STI571 (imatinib) prevents this ACM-hSOD1G93A-mediated motoneuron death. Interestingly, similar results were obtained with ACM derived from astrocytes expressing SOD1G86Ror TDP43A315T. We further find that co-application of ACM-SOD1G93Awith blockers of Nav channels (spermidine, mexiletine, or riluzole) or anti-oxidants (Trolox, esculetin, or tiron) effectively prevent c-Abl activation and motoneuron death. In addition, ACM-SOD1G93Ainduces alterations in the morphology of neuronal mitochondria that are related with their membrane depolarization. Finally, we find that blocking the opening of the mitochondrial permeability transition pore with cyclosporine A, or inhibiting mitochondrial calcium uptake with Ru360, reduces ROS production and c-Abl activation. Together, our data point to a sequence of events in which a toxic factor(s) released by ALS-expressing astrocytes rapidly induces hyper-excitability, which in turn increases calcium influx and affects mitochondrial structure and physiology. ROS production, mediated at least in part through mitochondrial alterations, trigger c-Abl signaling and lead to motoneuron death.

AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which pathogenesis and death of motor neurons are triggered by non-cell-autonomous mechanisms. We showed earlier that exposing primary rat spinal cord cultures to conditioned media derived from primary mouse astrocyte conditioned media (ACM) that express human SOD1G93A(ACM-hSOD1G93A) quickly enhances Nav channel- mediated excitability and calcium influx, generates intracellular reactive oxygen species (ROS), and leads to death of motoneurons within days. Here we examined the role of mitochondrial structure and physiology and of the activation of c-Abl, a tyrosine kinase that induces apoptosis. We show that ACM-hSOD1G93A, but not ACM-hSOD1WT, increases c-Abl activity in motoneurons, interneurons and glial cells, starting at 60 min; the c-Abl inhibitor STI571 (imatinib) prevents this ACM-hSOD1G93A-mediated motoneuron death. Interestingly, similar results were obtained with ACM derived from astrocytes expressing SOD1G86Ror TDP43A315T. We further find that co-application of ACM-SOD1G93Awith blockers of Nav channels (spermidine, mexiletine, or riluzole) or anti-oxidants (Trolox, esculetin, or tiron) effectively prevent c-Abl activation and motoneuron death. In addition, ACM-SOD1G93Ainduces alterations in the morphology of neuronal mitochondria that are related with their membrane depolarization. Finally, we find that blocking the opening of the mitochondrial permeability transition pore with cyclosporine A, or inhibiting mitochondrial calcium uptake with Ru360, reduces ROS production and c-Abl activation. Together, our data point to a sequence of events in which a toxic factor(s) released by ALS-expressing astrocytes rapidly induces hyper-excitability, which in turn increases calcium influx and affects mitochondrial structure and physiology. ROS production, mediated at least in part through mitochondrial alterations, trigger c-Abl signaling and lead to motoneuron death.

KW - ALS

KW - C-Abl

KW - Mitochondria

KW - Motor neuron

KW - Non-cell-autonomous

KW - Reactive oxygen species (ROS)

UR - http://www.scopus.com/inward/record.url?scp=84935850625&partnerID=8YFLogxK

U2 - 10.3389/fncel.2015.00203

DO - 10.3389/fncel.2015.00203

M3 - Article

AN - SCOPUS:84935850625

VL - 9

SP - 1

EP - 20

JO - Frontiers in Cellular Neuroscience

JF - Frontiers in Cellular Neuroscience

SN - 1662-5102

IS - June

M1 - A203

ER -