In:
Journal of Neurochemistry, Wiley, Vol. 148, No. 3 ( 2019-02), p. 426-439
Abstract:
Glutathione peroxidase 4 ( GP x4) is the only enzyme capable of reducing toxic lipid hydroperoxides in biological membranes to the corresponding alcohols using glutathione as the electron donor. GP x4 is the major inhibitor of ferroptosis, a non‐apoptotic and iron‐dependent programmed cell death pathway, which has been shown to occur in various neurological disorders with severe oxidative stress. In this study, we investigate whether GP x4 expression is altered in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis ( EAE ). The results clearly show that mRNA expression for all three GP x4 isoforms (cytoplasmic, mitochondrial and nuclear) decline in multiple sclerosis gray matter and in the spinal cord of MOG 35–55 peptide‐induced EAE . The amount of GP x4 protein is also reduced in EAE , albeit not in all cells. Neuronal GP x4 immunostaining, mostly cytoplasmic, is lower in EAE spinal cords than in control spinal cords, while oligodendrocyte GP x4 immunostaining, mainly nuclear, is unaltered. Neither control nor EAE astrocytes and microglia cells show GP x4 labeling. In addition to GP x4, two other negative modulators of ferroptosis (γ‐glutamylcysteine ligase and cysteine/glutamate antiporter), which are critical to maintain physiological levels of glutathione, are diminished in EAE . The decrease in the ability to eliminate hydroperoxides was also evidenced by the accumulation of lipid peroxidation products and the reduction in the proportion of the docosahexaenoic acid in non‐myelin lipids. These findings, along with presence of abnormal neuronal mitochondria morphology, which includes an irregular matrix, disrupted outer membrane and reduced/absent cristae, are consistent with the occurrence of ferroptotic damage in inflammatory demyelinating disorders. image
Type of Medium:
Online Resource
ISSN:
0022-3042
,
1471-4159
DOI:
10.1111/jnc.2019.148.issue-3
Language:
English
Publisher:
Wiley
Publication Date:
2019
detail.hit.zdb_id:
2020528-4
SSG:
12
Bookmarklink