Publication: Targeting WNT, protein kinase B,
and mitochondrial membrane integrity to
foster cellular survival in the nervous system
Authors
Chong, Z.Z. ; Maiese, K.
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
Targeting essential cellular pathways that
determine neuronal and vascular survival can foster a
successful therapeutic platform for the treatment of a
wide variety of degenerative disorders in the central
nervous system. In particular, oxidative cellular injury
can precipitate several nervous system disorders that
may either be acute in nature, such as during cerebral
ischemia, or more progressive and chronic, such as
during Alzheimer disease. Apoptotic injury in the brain
proceeds through two distinct pathways that ultimately
result in the early externalization of membrane
phosphatidylserine (PS) residues and the late induction
of genomic DNA fragmentation. Degradation of DNA
may acutely impact cellular survival, while the exposure
of membrane PS residues can lead to microglial
phagocytosis of viable cells, cellular inflammation, and
thrombosis in the vascular system. Through either
independent or common pathways, the Wingless/Wnt
pathway and the serine-threonine kinase Akt serve
central roles in the maintenance of cellular integrity and
the prevention of the phagocytic disposal of cells
"tagged" by PS exposure. By selectively governing the
activity of specific downstream substrates that include
GSK-3ß, Bad, and ß-catenin, Wnt and Akt serve to
foster neuronal and vascular survival and block the
induction of programmed cell death. Novel to Akt is its
capacity to protect cells from phagocytosis through the
direct modulation of membrane PS exposure. Intimately
linked to the activation of Wnt signaling and Akt is the
maintenance of mitochondrial membrane potential and
the regulation of Bcl-xL, mitochondrial energy
metabolism, and cytochrome c release that can lead to
specific cysteine protease activation.
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