Abstract
Oxidative stress has been proposed as a major mechanism of damage to motor neurons associated with the progression of amyotrophic lateral sclerosis (ALS). Astrocytes are the most numerous glial cells in the central nervous system and, under physiological conditions, protect neurons from oxidative damage. However, it is uncertain how their reactive phenotype may affect motor neurons during ALS progression. In two different ALS mouse models (SOD1G93A and FUS-R521C), we found that increased levels of proinflammatory interleukin 6 facilitate glutathione (GSH) release from the liver to blood circulation, which can reach the astrocytes and be channeled towards motor neurons as a mechanism of antioxidant protection. Nevertheless, although ALS progression is associated with an increase in GSH efflux from astrocytes, generation of reactive oxygen species also increases, suggesting that as the disease progresses, astrocyte-derived oxidative stress could be key to motor-neuron damage.
Highlights
Amyotrophic lateral sclerosis is a disease of the central nervous system (CNS)characterized by a progressive degeneration of motor neurons (MNs) in the cerebral cortex, brainstem and spinal cord [1]
We found that Interleukin 6 (IL6) plays a role in inducing the release of liver GSH in models of metastatic melanoma [14]
We found that treatment with anti-IL6 mAbs is associated with an increase in GSH levels in the liver (Table 3)
Summary
Amyotrophic lateral sclerosis (or ALS) is a disease of the central nervous system (CNS)characterized by a progressive degeneration of motor neurons (MNs) in the cerebral cortex (upper MNs), brainstem and spinal cord (lower MNs) [1]. Amyotrophic lateral sclerosis (or ALS) is a disease of the central nervous system (CNS). In the pathophysiology of the disease, neuroinflammation and oxidative stress are main mechanisms leading to neurodegeneration and MN death [4]. Progression of the disease is associated with reactive glia- and immunity-dependent neuroinflammation [5]. An increase in levels of inflammation-related cytokines can be detected in the cerebrospinal fluid (CSF) and blood of murine models and ALS patients [6]. It is difficult to evaluate inflammation of the CNS or the relationship between neuroinflammation and disease progression in ALS patients, it has been reported that the common IL6 receptor 358 Ala variant (IL6R358Ala) and trans-signaling are disease modifiers in ALS [7]
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