Oligodendrocyte progenitor programming and reprogramming: Toward myelin regeneration

Juarez, Alejandro Lopez; He, Danyang; Lü, Qing

doi:10.1016/j.brainres.2015.10.051

Cited by 46 publications

(36 citation statements)

References 122 publications

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“…OLs are the myelin producing cells of the CNS and are essential for proper brain function (Lopez Juarez et al, 2016; Simons and Nave, 2016). Mitochondria have been found to be located in different compartments of the OLs including soma, primary processes and the cytoplasmic channels of the myelin sheath (Rinholm et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Drp1 hyper-activation is protective in animal models of experimental multiple sclerosis

Luo

Herrup

et al. 2017

Experimental Neurology

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Multiple Sclerosis (MS), a leading neurological disorder of young adults, is characterized by the loss of oligodendrocytes (OLs), demyelination, inflammation and neuronal degeneration. Here we show that dynamin-related protein 1 (Drp1), a mitochondrial fission protein, is activated in primary OL cells exposed to TNF-α induced inflammation or oxidative stress, as well as in EAE-immunized and cuprizone toxicity-induced demyelinating mouse models. Inhibition of Drp1 hyper-activation by the selective inhibitor P110 abolishes Drp1 translocation to the mitochondria, reduces mitochondrial fragmentation and stems necrosis in primary OLs exposed to TNF-α and H2O2. Notably, in both types of mouse models, treatment with P110 significantly reduces the loss of mature OLs and demyelination, attenuates the number of active microglial cells and astrocytes, yet has no effect on the differentiation of oligodendrocyte precursor cells. Drp1 activation appears to be mediated through the RIPK1/RIPK3/MLKL/PGAM5 pathway during TNF-α-induced oligodendroglia necroptosis. Our results demonstrate a critical role of Drp1 hyper-activation in OL cell death and suggest that an inhibitor of Drp1 hyper-activation such as P110 is worth exploring for its ability to halt or slow the progression of MS.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Drp1 hyper-activation is protective in animal models of experimental multiple sclerosis

Luo

Herrup

et al. 2017

Experimental Neurology

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“…Many of the signaling pathways and trophic factors important in the specification, proliferation, and differentiation of OPCs during development also play a crucial role in repair of the adult injured brain [75,76]. In vivo time-lapse imaging in mice revealed that adult OPCs migrate to areas of focal demyelination and participate in tissue repair by generating new OLs to restore myelin [7].…”

Section: Myelin Plasticity Throughout Lifementioning

confidence: 99%

All Wrapped Up: Environmental Effects on Myelination

Forbes

Gallo

2017

Trends in Neurosciences

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Summary To date, studies have demonstrated the dynamic influence of exogenous environmental stimuli on multiple regions of the brain. This environmental influence positively and negatively impacts programs governing myelination, and acts on myelinating oligodendrocyte (OL) cells across the entire human lifespan. Developmentally, environmental manipulation of OL progenitor cells (OPCs) has profound effects on the establishment of functional cognitive, sensory, and motor programs. Furthermore, central nervous system (CNS) myelin remains an adaptive entity in adulthood, sensitive to environmentally induced structural changes. Here, we discuss the role of environmental stimuli on mechanisms governing programs of CNS myelination under normal and pathological conditions. Importantly, we highlight how these extrinsic cues can influence the intrinsic power of myelin plasticity to promote functional recovery.

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“…In addition, ERK1/2-MAPK (mitogen-activated protein kinase) [43] regulates myelin thickness, independent of OL differentiation, and myelination initiation [44]. The other signaling pathways and molecules behind impaired remyelination in animal models include involvement of the Notch1, LINGO1, wnt/β catenin, and hyaluronan/TLR2 pathways (reviews [45] [46]).…”

Section: Stimulating Functional Remyelinationmentioning

confidence: 99%

Nudging oligodendrocyte intrinsic signaling to remyelinate and repair: Estrogen receptor ligand effects

Khalaj

Hasselmann

Augello

et al. 2016

The Journal of Steroid Biochemistry and Molecular Biology

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Demyelination in multiple sclerosis (MS) leads to significant, progressive axonal and neuronal degeneration. Currently existing immunosuppressive and immunomodulatory therapies alleviate MS symptoms and slow, but fail to prevent or reverse, disease progression. Restoration of damaged myelin sheath by replenishment of mature oligodendrocytes (OLs) should not only restore saltatory axon conduction, but also provide a major boost to axon survival. Our previous work has shown that therapeutic treatment with the modestly selective generic estrogen receptor (ER) β agonist diarylpropionitrile (DPN) confers functional neuroprotection in a chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS by stimulating endogenous myelination. Recently, we found that the more potent, selective ERβ agonist indazole-chloride (Ind-Cl) improves clinical disease and motor performance. Importantly, electrophysiological measures revealed improved corpus callosal conduction and reduced axon refractoriness. This Ind-Cl treatment-induced functional remyelination was attributable to increased OL progenitor cell (OPC) and mature OL numbers. At the intracellular signaling level, transition of early to late OPCs requires Erk1/2 signaling, and transition of immature to mature OLs requires mTOR signaling; thus, the PI3K/Akt/mTOR pathway plays a major role in the late stages of OL differentiation and myelination. Indeed, therapeutic treatment of EAE mice with various ERβ agonists results in increased brain-derived neurotrophic factor (BDNF) and phosphorylated (p) Akt and p-mTOR levels. It is notable that while DPN’s neuroprotective effects occur in the presence of peripheral and central inflammation, Ind-Cl is directly neuroprotective, as demonstrated by remyelination effects in the cuprizone-induced demyelination model, as well as anti-inflammatory. Elucidating the mechanisms by which ER agonists and other directly remyelinating agents modulate endogenous OPC and OL regulatory signaling is critical to the development of effective remyelinating drugs. The discovery of signaling targets to induce functional remyelination will valuably contribute to the treatment of demyelinating neurological diseases, including MS, stroke, and traumatic brain and spinal cord injury.

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Oligodendrocyte progenitor programming and reprogramming: Toward myelin regeneration

Cited by 46 publications

References 122 publications

Inhibition of Drp1 hyper-activation is protective in animal models of experimental multiple sclerosis

Inhibition of Drp1 hyper-activation is protective in animal models of experimental multiple sclerosis

All Wrapped Up: Environmental Effects on Myelination

Nudging oligodendrocyte intrinsic signaling to remyelinate and repair: Estrogen receptor ligand effects

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