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

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

dc.contributor.author	Rojas, Fabiola
dc.contributor.author	Gonzalez, David
dc.contributor.author	Cortes, Nicole
dc.contributor.author	Ampuero, Estibaliz
dc.contributor.author	Hernández, Diego E
dc.contributor.author	Fritz, Elsa
dc.contributor.author	Abarzua, Sebastián
dc.contributor.author	Martinez, Alexis
dc.contributor.author	Elorza, Alvaro A.
dc.contributor.author	Alvarez, Alejandra
dc.contributor.author	Court, Felipe
dc.contributor.author	Van Zundert, Brigitte
dc.date.accessioned	2023-05-18T16:14:41Z
dc.date.available	2023-05-18T16:14:41Z
dc.date.issued	2015-06
dc.description	Indexación: Scopus	es
dc.description.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. © 2015 Rojas,Gonzalez,Cortes	es
dc.description.uri	https://www.frontiersin.org/articles/10.3389/fncel.2015.00203/full
dc.identifier.citation	Frontiers in Cellular Neuroscience Volume 9, Issue June, Pages 1 - 209 June 2015 Article number A203	es
dc.identifier.doi	10.3389/fncel.2015.00203
dc.identifier.issn	1662-5102
dc.identifier.uri	https://repositorio.unab.cl/xmlui/handle/ria/49782
dc.language.iso	en	es
dc.publisher	Frontiers Research Foundation	es
dc.rights.license	Atribución 4.0 Internacional (CC BY 4.0)
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/deed.es
dc.subject	ALS	es
dc.subject	C-Abl	es
dc.subject	Mitochondria	es
dc.subject	Motor neuron	es
dc.subject	Non-cell-autonomous	es
dc.subject	Reactive oxygen species (ROS)	es
dc.title	Reactive oxygen species trigger motoneuron death in non-cell-autonomous models of als through activation of c-Abl signaling	es
dc.type	Artículo	es