Oligodendrocyte Death in Pelizaeus-Merzbacher Disease Is Rescued by Iron Chelation

Nobuta, Hiroko; Yang, Nan; Ng, Yi Han; Marro, Samuele; Sabeur, Khalida; Chavali, Manideep; Stockley, John H.; Killilea, David W.; Walter, Patrick; Zhao, Chao; Huie, Philip; Goldman, Steven A.; Kriegstein, Arnold R.; Franklin, R. J. M.; Rowitch, David H.; Wernig, Marius

doi:10.1016/j.stem.2019.09.003

Cited by 67 publications

(54 citation statements)

References 37 publications

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“…Hemoglobin-and hemin-induced toxicity reportedly involve both ferroptosis and necroptosis. 175,176 Iron overloadinduced ferroptosis is implicated in Pelizaeus-Merzbacher disease caused by mutations in proteolipid protein 1 (PLP1) 177 or neuroferritinopathy. 178 The ferroptosis inhibitor SRS11-92 is highly effective in protecting human primary fibroblasts from cell death induced by frataxin depletion, indicating that targeting ferroptosis might be useful for the treatment of Friedreich ataxia, pending confirmation in animal models.…”

Section: Nervous Systemmentioning

confidence: 99%

Ferroptosis: molecular mechanisms and health implications

et al. 2020

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Cell death can be executed through different subroutines. Since the description of ferroptosis as an iron-dependent form of non-apoptotic cell death in 2012, there has been mounting interest in the process and function of ferroptosis. Ferroptosis can occur through two major pathways, the extrinsic or transporter-dependent pathway and the intrinsic or enzyme-regulated pathway. Ferroptosis is caused by a redox imbalance between the production of oxidants and antioxidants, which is driven by the abnormal expression and activity of multiple redox-active enzymes that produce or detoxify free radicals and lipid oxidation products. Accordingly, ferroptosis is precisely regulated at multiple levels, including epigenetic, transcriptional, posttranscriptional and posttranslational layers. The transcription factor NFE2L2 plays a central role in upregulating anti-ferroptotic defense, whereas selective autophagy may promote ferroptotic death. Here, we review current knowledge on the integrated molecular machinery of ferroptosis and describe how dysregulated ferroptosis is involved in cancer, neurodegeneration, tissue injury, inflammation, and infection.

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Section: Nervous Systemmentioning

confidence: 99%

Ferroptosis: molecular mechanisms and health implications

et al. 2020

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“…Using an in vitro method of mixed glial cultures of astrocytes and oligodendrocytes (McCarthy & de Vellis, 1980), Martin Raff and colleagues found that astrocyte-derived platelet-derived growth factor (PDGF) was essential for regulating oligodendrocyte differentiation (Raff, Lillien, Richardson, Burne, & Noble, 1988). Another example is the importance of iron metabolism, in particular the role of transferrin and ferritin, in oligodendrocyte development (Espinosa de los Monteros et al, 1999;Nobuta et al, 2019). These findings also provided an important stepping-stone for the nowadays in vitro culture methods used for oligodendrocyte development studies (Azevedo et al, 2018;Boucanova et al, 2018;Y.…”

Section: Oligodendrocyte Progenitor Cells/oligodendrocyte and Type-mentioning

confidence: 99%

Glial restricted precursor cells in central nervous system disorders: Current applications and future perspectives

Macedo

Lepore

Domingues

et al. 2020

Glia

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The crosstalk between glial cells and neurons represents an exceptional feature for maintaining the normal function of the central nervous system (CNS). Increasing evidence has revealed the importance of glial progenitor cells in adult neurogenesis, reestablishment of cellular pools, neuroregeneration, and axonal (re)myelination. Several types of glial progenitors have been described, as well as their potentialities for recovering the CNS from certain traumas or pathologies. Among these precursors, glial‐restricted precursor cells (GRPs) are considered the earliest glial progenitors and exhibit tripotency for both Type I/II astrocytes and oligodendrocytes. GRPs have been derived from embryos and embryonic stem cells in animal models and have maintained their capacity for self‐renewal. Despite the relatively limited knowledge regarding the isolation, characterization, and function of these progenitors, GRPs are promising candidates for transplantation therapy and reestablishment/repair of CNS functions in neurodegenerative and neuropsychiatric disorders, as well as in traumatic injuries. Herein, we review the definition, isolation, characterization and potentialities of GRPs as cell‐based therapies in different neurological conditions. We briefly discuss the implications of using GRPs in CNS regenerative medicine and their possible application in a clinical setting.Main PointsGRPs are progenitors present in the CNS with differentiation potential restricted to the glial lineage. These cells have been employed in the treatment of a myriad of neurodegenerative and traumatic pathologies, accompanied by promising results, herein reviewed.

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“…To date, no effective treatment is available for PMD, although deferiprone, an iron chelator, reduced oligodendrocyte apoptosis and facilitated myelin formation in the jimpy mouse model of connatal PMD ( Nobuta et al , 2019 ), and ketogenic diet ( Stumpf et al , 2019 ), cholesterol supplementation ( Saher et al , 2012 ) and transcriptional suppression by artificial microRNA ( Li et al , 2019 ) have proven beneficial in Plp1 -overexpressing animal models. Stem cell therapy for PMD has undergone a clinical safety trial in four patients with connatal forms due to point mutations in the PLP1 gene, in whom myelin is absent by MRI ( Gupta et al , 2012 , 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Neural stem cells restore myelin in a demyelinating model of Pelizaeus-Merzbacher disease

Gruenenfelder

McLaughlin

Griffiths

et al. 2020

Brain

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Pelizaeus-Merzbacher disease is a fatal X-linked leukodystrophy caused by mutations in the PLP1 gene, which is expressed in the CNS by oligodendrocytes. Disease onset, symptoms and mortality span a broad spectrum depending on the nature of the mutation and thus the degree of CNS hypomyelination. In the absence of an effective treatment, direct cell transplantation into the CNS to restore myelin has been tested in animal models of severe forms of the disease with failure of developmental myelination, and more recently, in severely affected patients with early disease onset due to point mutations in the PLP1 gene, and absence of myelin by MRI. In patients with a PLP1 duplication mutation, the most common cause of Pelizaeus-Merzbacher disease, the pathology is poorly defined because of a paucity of autopsy material. To address this, we examined two elderly patients with duplication of PLP1 in whom the overall syndrome, including end-stage pathology, indicated a complex disease involving dysmyelination, demyelination and axonal degeneration. Using the corresponding Plp1 transgenic mouse model, we then tested the capacity of transplanted neural stem cells to restore myelin in the context of PLP overexpression. Although developmental myelination and axonal coverage by endogenous oligodendrocytes was extensive, as assessed using electron microscopy (n = 3 at each of four end points) and immunostaining (n = 3 at each of four end points), wild-type neural precursors, transplanted into the brains of the newborn mutants, were able to effectively compete and replace the defective myelin (n = 2 at each of four end points). These data demonstrate the potential of neural stem cell therapies to restore normal myelination and protect axons in patients with PLP1 gene duplication mutation and further, provide proof of principle for the benefits of stem cell transplantation for other fatal leukodystrophies with ‘normal’ developmental myelination.

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Oligodendrocyte Death in Pelizaeus-Merzbacher Disease Is Rescued by Iron Chelation

Abstract: Highlights d PLP1 mutations in Pelizaeus-Merzbacher disease cause ironinduced oligodendrocyte death d Gene correction in patient-derived iPSCs rescues PLP1 mutant oligodendrocyte cell death d Iron chelators and lipophilic antioxidants rescue mutant oligodendrocyte cell death

Cited by 67 publications

References 37 publications

Ferroptosis: molecular mechanisms and health implications

Ferroptosis: molecular mechanisms and health implications

Glial restricted precursor cells in central nervous system disorders: Current applications and future perspectives

Neural stem cells restore myelin in a demyelinating model of Pelizaeus-Merzbacher disease

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