Astrocytes expressing mutant SOD1 and TDP43 trigger motoneuron death that is mediated via sodium channels and nitroxidative stress
Cargando...
Archivos
Fecha
2014-02
Profesor/a Guía
Facultad/escuela
Idioma
en
Título de la revista
ISSN de la revista
Título del volumen
Editor
Frontiers Research Foundation
Nombre de Curso
Licencia CC
Atribution 4.0 International (CC BY 4.0)
Licencia CC
https://creativecommons.org/licenses/by/4.0/deed.es
Resumen
Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disorder caused by dysfunction
and degeneration of motor neurons. Multiple disease-causing mutations, including in the
genes for SOD1 and TDP-43, have been identified in ALS. Astrocytes expressing mutant
SOD1 are strongly implicated in the pathogenesis of ALS: we have shown that media
conditioned by astrocytes carrying mutant SOD1G93A contains toxic factor(s) that kill
motoneurons by activating voltage-sensitive sodium (Nav ) channels. In contrast, a recent
study suggests that astrocytes expressing mutated TDP43 contribute to ALS pathology,
but do so via cell-autonomous processes and lack non-cell-autonomous toxicity. Here we
investigate whether astrocytes that express diverse ALS-causing mutations release toxic
factor(s) that induce motoneuron death, and if so, whether they do so via a common
pathogenic pathway. We exposed primary cultures of wild-type spinal cord cells to
conditioned medium derived from astrocytes (ACM) that express SOD1 (ACM-SOD1G93A
and ACM-SOD1G86R) or TDP43 (ACM-TDP43A315T) mutants; we show that such exposure
rapidly (within 30–60 min) increases dichlorofluorescein (DCF) fluorescence (indicative of
nitroxidative stress) and leads to extensive motoneuron-specific death within a few days.
Co-application of the diverse ACMs with anti-oxidants Trolox or esculetin (but not with
resveratrol) strongly improves motoneuron survival. We also find that co-incubation of
the cultures in the ACMs with Nav channel blockers (including mexiletine, spermidine, or
riluzole) prevents both intracellular nitroxidative stress and motoneuron death. Together,
our data document that two completely unrelated ALS models lead to the death of
motoneuron via non-cell-autonomous processes, and show that astrocytes expressing
mutations in SOD1 and TDP43 trigger such cell death through a common pathogenic
pathway that involves nitroxidative stress, induced at least in part by Nav channel activity.
Notas
Indexación: Scopus.
Palabras clave
ALS, Non-Cell-Autonomous, Motor Neuron, Degeneration, ROS/RNS, Anti-oxidants
Citación
Frontiers in Cellular Neuroscience. Volume 8, Issue FEB. 7 February 2014. Article number 24
DOI
10.3389/fncel.2014.00024