Peptide regulation of cofilin activity in the CNS: A novel therapeutic approach for treatment of multiple neurological disorders

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http://www.sciencedirect.com/science/article/pii/S0163725817300451

• Alisa E. Shaw,
• James R. Bamburg^,

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http://dx.doi.org/10.1016/j.pharmthera.2017.02.031

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Abstract

Cofilin is a ubiquitous protein which cooperates with many other actin-binding proteins in regulating actin dynamics. Cofilin has essential functions in nervous system development including neuritogenesis, neurite elongation, growth cone pathfinding, dendritic spine formation, and the regulation of neurotransmission and spine function, components of synaptic plasticity essential for learning and memory. Cofilin's phosphoregulation is a downstream target of many transmembrane signaling processes, and its misregulation in neurons has been linked in rodent models to many different neurodegenerative and neurological disorders including Alzheimer disease (AD), aggression due to neonatal isolation, autism, manic/bipolar disorder, and sleep deprivation. Cognitive and behavioral deficits of these rodent models have been largely abrogated by modulation of cofilin activity using viral-mediated, genetic, and/or small molecule or peptide therapeutic approaches. Neuropathic pain in rats from sciatic nerve compression has also been reduced by modulating the cofilin pathway within neurons of the dorsal root ganglia. Neuroinflammation, which occurs following cerebral ischemia/reperfusion, but which also accompanies many other neurodegenerative syndromes, is markedly reduced by peptides targeting specific chemokine receptors, which also modulate cofilin activity. Thus, peptide therapeutics offer potential for cost-effective treatment of a wide variety of neurological disorders. Here we discuss some recent results from rodent models using therapeutic peptides with a surprising ability to cross the rodent blood brain barrier and alter cofilin activity in brain. We also offer suggestions as to how neuronal-specific cofilin regulation might be achieved.

Abbreviations

• Aβ, β-amyloid peptide produced from amyloid precursor protein in AD;
• AD, Alzheimer disease;
• ADF, actin depolymerizing factor;
• AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid;
• APP, amyloid precursor protein;
• APPsw, human APP with Swedish mutation;
• Arp2/3 complex, actin-related proteins 2/3 complex;
• CCR2 and CCR5, G-protein coupled chemokine receptors;
• CIN, chronophin, a cofilin phosphatase (aka pyridoxal-5′-phosphate phosphatase);
• CNS, central nervous system;
• CPP, cell penetrating peptide;
• CTD, C-terminal domain;
• DAPTA, d-ala peptide T-amide (d-ala-STTTNYT-amide);
• DOCK, dedicator of cytokinesis;
• DS, Down syndrome;
• F-actin, filamentous actin;
• G-actin, globular actin (monomeric);
• HIV, human immunodeficiency virus;
• LIMK, a cofilin kinase with a LIM domain;
• LTD, long-term depression;
• LTP, long-term potentiation;
• nArgBP2, neural Abelson-related gene-binding protein 2, product of the Sorbs2 gene NLG1: neuroligin 1;
• NMDA, N-methyl-d-aspartate;
• NOX, NADPH oxidase;
• Pak, p21-activated kinase;
• PDZ, a structural domain first identified in the proteins PSD-95, Dlg1 and ZO-1;
• PKCα, protein kinase C alpha;
• PP2B, protein phosphatase 2B (aka calcineurin);
• PrP^C, cellular prion protein;
• PS1₂, presenilin 1 with M146L and L286V mutations;
• PS1ΔE9, human presenilin 1 missing exon 9;
• pS3 peptide, the S3 peptide phosphorylated on serine 3;
• RanBP9, Ran binding protein 9;
• RAP-310, an all D-amino acid version of DAPTA;
• ROCK, Rho kinase;
• ROS, reactive oxygen species;
• S3 peptide, The N-terminal 16 amino acids of mammalian cofilin;
• Shank3, SH3 and multiple Ankyrin repeat domains 3, also known as ProSAP2;
• SPAR, spine-associated Rap GTPase-activating protein;
• Srv2, named for suppressor of RAS2-val19 allele 2. Also known as cyclase associated protein (CAP or Srv2/CAP);
• SSH, slingshot phosphatase;
• TAT, transactivator of transcription from the human immunodeficiency virus;
• Tβ4, thymosin β4;
• Tpm, tropomyosin;
• WAVE1, Wiskott-Aldrich Syndrome protein-family verprolin homologous protein 1

Keywords

• Dendritic spines;
• Cofilin phosphoregulation;
• Cognitive disorders;
• Psychiatric disorders;
• Neuropathic pain;
• Sleep deprivation;
• Rodent models

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Corresponding author at: Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523-1870, United States.