MAG and myelin block the ability of BDNF to overcome inhibition of axonal regeneration by inhibiting BDNF's activation of Rap1
Item
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Title
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MAG and myelin block the ability of BDNF to overcome inhibition of axonal regeneration by inhibiting BDNF's activation of Rap1
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Identifier
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d_2009_2013:d9ee69aa8446:10275
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identifier
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10453
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Creator
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Gkioka, Vasiliki,
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Contributor
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Marie T. Filbin
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Date
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2009
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Language
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English
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Publisher
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City University of New York.
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Subject
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Neurosciences | Cellular biology | Molecular biology | axonal | BDNF | MAG | myelin | Rap1 | regeneration
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Abstract
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It is well established that axons of the adult mammalian CNS do not regenerate if injured by trauma, or if afflicted by various neurodegenerative conditions. It is also well established that myelin, the insulating and protective membranous sheath around neurons, contains several proteins that act as inhibitors of neurite outgrowth, such as MAG, and damaged myelin is one of the factors limiting CNS regeneration after injury. Because of their well established role in neuronal development, survival, and function, neurotrophins have been candidates for therapeutic intervention in the nervous system for many years, and have already been used in clinical trials for various neurological conditions.;We have previously shown that neurotrophins elevate cAMP. If the cAMP signaling cascade is initiated in neurons exposed to MAG and myelin, with the non-hydrolyzable analogue dibutyryl-cAMP, inhibition of neurite outgrowth by both is blocked in vitro. Importantly, we have shown that if cAMP is elevated in damaged neurons, nerve regeneration is promoted in vivo. We have also observed that neurotrophin-induced cAMP elevation is blocked in the presence of MAG, and neurotrophins are effective in overcoming MAG inhibition only by overnight pre-exposure of neurons to them, a procedure we call "priming with neurotrophins". Therefore, understanding the mechanism of MAG and myelin's block of neurotrophin signaling could result in the design of therapeutics that target only specific molecules in the neurotrophin cascade, in order to potentiate only specific and desirable effects of neurotrophins, for specific types of injury or disease. We have found that MAG and myelin block the BDNF activation of Rap1, one of the Ras-superfamily members activated in the neurotrophin cascade, which is also part of the cAMP signaling network, due to cAMP-activation of one of its upstream activators, EPAC.;We have also shown that MAG and myelin treatment of neurons results in upregulation of the protein levels of the Rap1 inactivator Rap1GAP, which provides a mechanism for the block of Rap1 activation by BDNF. Additionally we have shown that priming of neurons with the EPAC-specific cAMP analogue 8-CPT-2Me-cAMP, like priming with neurotrophins, is sufficient to overcome inhibition by MAG. Moreover, infection of neurons with adenoviruses carrying wild type Rap1, or the RapGAP insensitive mutant Rap1F64A, improved growth on MAG and myelin. Infection of neurons with adenovirus carrying the Rap1 inactivator Rap1GAPI blocked the ability of neurons to extend neurites, demonstrating an essential role of the Rap1 family in regulating neurite outgrowth.;Besides its implications for therapeutic intervention after CNS trauma, the modulation of the neurotrophin cascade by MAG demonstrated here might be a new manifestation of the role of MAG and myelin in restricting plasticity in the intact CNS.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biology
