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Iron In Multiple Sclerosis Animal Model
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ironjustice
Jan 2, 2021, 7:40:06 PM1/2/21
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Ferroptosis mediates cuprizone-induced loss of oligodendrocytes and demyelination
Priya Jhelum, Eva Santos-Nogueira, Wulin Teo, Alice Haumont, Isadora Lenoël, Peter K Stys, Samuel David
Journal of Neuroscience 2020 October 26
Multiple sclerosis (MS) is a chronic demyelinating disease of the CNS. Cuprizone (CZ), a copper chelator, is widely used to study demyelination and remyelination in the CNS, in the context of MS. However, the mechanisms underlying oligodendrocyte (OL) cell loss and demyelination are not known. As copper containing enzymes play important roles in iron homeostasis and controlling oxidative stress, we examined if chelating copper leads to disruption of molecules involved in iron homeostasis that can trigger iron mediated OL loss. We show that giving mice CZ in the diet induces rapid loss of OL in the corpus callosum by 2 days, accompanied by expression of several markers for ferroptosis, a relatively newly described form of iron-mediated cell death. In ferroptosis, iron-mediated free radicals trigger lipid peroxidation under conditions of glutathione insufficiency, and a reduced capacity to repair lipid damage. This was further confirmed using a small molecule inhibitor of ferroptosis that prevents CZ-induced loss of OL and demyelination, providing clear evidence of a copper-iron connection in CZ-induced neurotoxicity. This work has wider implications for disorders such as multiple sclerosis and CNS injury. SIGNIFICANCE STATEMENT Cuprizone (CZ) is a copper chelator that induces demyelination. Although it is a widely used model to study demyelination and remyelination in the context of multiple sclerosis (MS), the mechanisms mediating demyelination is not fully understood. This study shows for the first time that CZ induces demyelination via ferroptosis-mediated rapid loss of oligodendrocytes. This work shows that chelating copper with CZ leads to the expression of molecules that rapidly mobilize iron from ferritin (an iron storage protein), that triggers iron-mediated lipid peroxidation and oligodendrocyte loss (via ferroptosis). Such rapid mobilization of iron from cellular stores may also play a role in cell death in other neurological conditions.
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Priya Jhelum, Eva Santos-Nogueira, Wulin Teo, Alice Haumont, Isadora Lenoël, Peter K Stys, Samuel David
Journal of Neuroscience 2020 October 26
Multiple sclerosis (MS) is a chronic demyelinating disease of the CNS. Cuprizone (CZ), a copper chelator, is widely used to study demyelination and remyelination in the CNS, in the context of MS. However, the mechanisms underlying oligodendrocyte (OL) cell loss and demyelination are not known. As copper containing enzymes play important roles in iron homeostasis and controlling oxidative stress, we examined if chelating copper leads to disruption of molecules involved in iron homeostasis that can trigger iron mediated OL loss. We show that giving mice CZ in the diet induces rapid loss of OL in the corpus callosum by 2 days, accompanied by expression of several markers for ferroptosis, a relatively newly described form of iron-mediated cell death. In ferroptosis, iron-mediated free radicals trigger lipid peroxidation under conditions of glutathione insufficiency, and a reduced capacity to repair lipid damage. This was further confirmed using a small molecule inhibitor of ferroptosis that prevents CZ-induced loss of OL and demyelination, providing clear evidence of a copper-iron connection in CZ-induced neurotoxicity. This work has wider implications for disorders such as multiple sclerosis and CNS injury. SIGNIFICANCE STATEMENT Cuprizone (CZ) is a copper chelator that induces demyelination. Although it is a widely used model to study demyelination and remyelination in the context of multiple sclerosis (MS), the mechanisms mediating demyelination is not fully understood. This study shows for the first time that CZ induces demyelination via ferroptosis-mediated rapid loss of oligodendrocytes. This work shows that chelating copper with CZ leads to the expression of molecules that rapidly mobilize iron from ferritin (an iron storage protein), that triggers iron-mediated lipid peroxidation and oligodendrocyte loss (via ferroptosis). Such rapid mobilization of iron from cellular stores may also play a role in cell death in other neurological conditions.
Who loves ya.
Tom
Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh
Man Is A Herbivore!
http://tinyurl.com/a3cc3
DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk
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