Modifying PTEN recruitment promotes neuron survival, regeneration, and functional recovery after CNS injury. 2019

Alireza Pirsaraei Shabanzadeh, and Philippe Matteo D'Onofrio, and Mark Magharious, and Kyung An Brian Choi, and Philippe Patrick Monnier, and Paulo Dieter Koeberle
Division of Anatomy, Department of Surgery, University of Toronto, Toronto, ON, M5S 1A8, Canada.

Phosphatase and tensin homolog (PTEN) regulates apoptosis and axonal growth in the developing and adult central nervous system (CNS). Here, we show that human PTEN C-terminal PDZ interactions play a critical role in neuronal apoptosis and axon regeneration after traumatic CNS injury and stroke, highlighted by the findings that antagonizing the PDZ-motif interactions of PTEN has therapeutic applicability for these indications. Interestingly, the death-inducing function of PTEN following ischemic insult depends on a PDZ-domain interaction with MAGI-2 and MAST205, PDZ proteins that are known to recruit PTEN to the plasma membrane and stabilize its interaction with PIP3. Treatments with a human peptide that prevents PTEN association with MAGI-2 or MAST205 increased neuronal survival in multiple stroke models, in vitro. A pro-survival effect was also observed in models of retinal ischemia, optic nerve transection, and after middle cerebral artery occlusion (MCAO) in adult rats. The human PTEN peptide also improved axonal regeneration in the crushed optic nerve. Furthermore, human PTEN peptide therapy promoted functional improvement after MCAO or retinal ischemia induced via ophthalmic artery ligation. These findings show that the human peptide-based targeting of C-terminal PTEN PDZ interactions has therapeutic potential for insults of the CNS, including trauma and stroke.

UI MeSH Term Description Entries
D009416 Nerve Regeneration Renewal or physiological repair of damaged nerve tissue. Nerve Tissue Regeneration,Nervous Tissue Regeneration,Neural Tissue Regeneration,Nerve Tissue Regenerations,Nervous Tissue Regenerations,Neural Tissue Regenerations,Regeneration, Nerve,Regeneration, Nerve Tissue,Regeneration, Nervous Tissue,Regeneration, Neural Tissue,Tissue Regeneration, Nerve,Tissue Regeneration, Nervous,Tissue Regeneration, Neural
D009900 Optic Nerve The 2nd cranial nerve which conveys visual information from the RETINA to the brain. The nerve carries the axons of the RETINAL GANGLION CELLS which sort at the OPTIC CHIASM and continue via the OPTIC TRACTS to the brain. The largest projection is to the lateral geniculate nuclei; other targets include the SUPERIOR COLLICULI and the SUPRACHIASMATIC NUCLEI. Though known as the second cranial nerve, it is considered part of the CENTRAL NERVOUS SYSTEM. Cranial Nerve II,Second Cranial Nerve,Nervus Opticus,Cranial Nerve, Second,Cranial Nerves, Second,Nerve, Optic,Nerve, Second Cranial,Nerves, Optic,Nerves, Second Cranial,Optic Nerves,Second Cranial Nerves
D010455 Peptides Members of the class of compounds composed of AMINO ACIDS joined together by peptide bonds between adjacent amino acids into linear, branched or cyclical structures. OLIGOPEPTIDES are composed of approximately 2-12 amino acids. Polypeptides are composed of approximately 13 or more amino acids. PROTEINS are considered to be larger versions of peptides that can form into complex structures such as ENZYMES and RECEPTORS. Peptide,Polypeptide,Polypeptides
D002470 Cell Survival The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D005260 Female Females
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000595 Amino Acid Sequence The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION. Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001369 Axons Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. Axon

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