Generic placeholder image

Current Psychopharmacology

Editor-in-Chief

ISSN (Print): 2211-5560
ISSN (Online): 2211-5579

Review Article

Protein Chimera-based Ca2+ Rewiring as a Treatment Modality for Neurodegeneration

Author(s): Netra Unni Rajesh and Anam Qudrat*

Volume 8, Issue 1, 2019

Page: [27 - 40] Pages: 14

DOI: 10.2174/2211556007666181001102702

Abstract

Calcium is a versatile signaling molecule; a key regulator of an array of diverse cellular processes ranging from transcription to motility to apoptosis. It plays a critical role in neuronal signal transmission and energy metabolism through specialized mechanisms. Dysregulation of the Ca2+ signaling pathways has been linked to major psychiatric diseases. Here, we focus on molecular psychiatry, exploring the role of calcium signaling in neurological disease development and aggravation, specifically in Alzheimer’s and Huntington’s diseases. Understanding the molecular underpinnings helps us first to identify common mechanistic patterns, and second to develop targeted therapeutics for symptom alleviation. Specifically, we propose potential protein-level hallmarks of dysregulation that can be targeted using calcium-based chimeras (synthetic fusions of unrelated modular proteins) for localized pharmacotherapy.

Keywords: Alzheimer's disease, calcium signalling dysregulation, cell-based therapeutics, Huntington's Disease, protein chimera, neurodegeneration.

Graphical Abstract
[1]
Wyss-Coray T. Ageing, neurodegeneration and brain rejuvenation. Nature 2016; 539(7628): 180-6.
[2]
Possin K. Visual spatial cognition in neurodegenerative disease. Neurocase 2010; 16(6): 466-87.
[3]
Pchitskaya E, Popugaeva E, Bezprozvanny I. Calcium signaling and molecular mechanisms underlying neurodegenerative diseases. Cell Calcium 2018; 70: 87-94.
[4]
Pilato F, Profice P, Ranieri F, et al. Synaptic plasticity in neurodegenerative diseases evaluated and modulated by in vivo neurophysiological techniques. Mol Neurobiol 2012; 46(3): 563-71.
[5]
Marambaud P, Dreses-Werringloer U, Vingtdeux V. Calcium signaling in neurodegeneration. Mol Neurodegener 2009; 4(1): 20.
[6]
Masters C, Bateman R, Blennow K, Rowe C, Sperling R, Cummings J. Alzheimer's disease. Nature Reviews Disease Primers [Internet]. 2015; 15056. Available from: http: //www.nature.com/articles/nrdp201556?WT.mc_id=LAN_ NRDP_1604_FIRSTANNIVERSARY [cited 6 January 2017].
[7]
Cunningham E, McGuinnness B, Herron B, Passmore A. Dementia. Ulster Medical Journal [Internet]. 2015; 84(2): 79-87. Available from: https: //www.ncbi.nlm.nih.gov/ pmc/articles/PMC4488926/ [cited 3 February 2017].
[8]
Scheltens P, Blennow K, Breteler MMB, et al. Alzheimer’s disease. The Lancet 2016; 388(10043): 505-17.
[9]
Geda YE, Schneider LS, Gitlin LN, et al. Neuropsychiatric symptoms in Alzheimer’s disease: Past progress and anticipation of the future. Alzheimers Dement 2013; 9(5): 602-8.
[10]
Ma J, Brewer Jr H.B., Potter H. Alzheimer Aβ neurotoxicity: Promotion by antichymotrypsin, ApoE4; Inhibition by Aβ-related peptides. Neurobiol Aging 1996; 17(5): 773-80.
[11]
Vetrivel KS, Thinakaran G. Membrane rafts in Alzheimer's disease beta-amyloid production BBA - Mole Cell Biol Lip 2010; 1801(8): 860-7.
[12]
Thompson J, Harris J, Sollom A, et al. Longitudinal evaluation of neuropsychiatric symptoms in huntington’s disease. J Neuropsychiatry Clin Neurosci 2012; 24(1): 53-60.
[13]
Fitzsimmons S, Jones L, Holmans P. Factors influencing the presence of behavioural symptoms in huntington's disease. J Neurol Neurosur Psychiatry 2015; 86(9): e3.29-e3.
[14]
Steffan J. SUMO modification of huntingtin and huntington’s disease pathology. Science 2004; 304(5667): 100-4.
[15]
Pidgeon C, Rickards H. The pathophysiology and pharmacological treatment of huntington disease. Behav Neurol 2013; 26(4): 245-53.
[16]
Ross C, Shoulson I. Huntington disease: Pathogenesis, biomarkers, and approaches to experimental therapeutics. Parkinsonism Relat Disord 2009; 15: S135-8.
[17]
LaFerla F. Calcium dyshomeostasis and intracellular signalling in alzheimer’s disease. Nat Rev Neurosci 2002; 3(11): 862-72.
[18]
Baumgartel K, Mansuy I. Neural functions of calcineurin in synaptic plasticity and memory. Learn Mem 2012; 19(9): 375-84.
[19]
Berridge M. Calcium hypothesis of Alzheimer’s disease. Pflügers Archiv - European Journal of Physiology [Internet]. 2009; 459(3): 441-449. Available from: https: //link.springer.com/article/10.1007/s00424-009-0736-1 [cited 20 January 2018].
[20]
Kolobova Y, Vigont V, Shalygin A, Kaznacheyeva E. Huntington’s disease: Calcium dyshomeostasis and pathology models. ActaNaturae [Internet]. 2017; 9(2): 34-46. Available from.https: //www.ncbi.nlm.nih.gov/pmc/articles/ PMC5508999/ [cited 20 January 2018].
[21]
Wang J, Chen Q, Wang X, et al. Dysregulation of mitochondrial calcium signaling and superoxide flashes cause mitochondrial genomic DNA damage in Huntington disease. J Biol Chem 2012; 288(5): 3070-84.
[22]
Zündorf G, Reiser G. Calcium dysregulation and homeostasis of neural calcium in the molecular mechanisms of neurodegenerative diseases provide multiple targets for neuroprotection. Antioxid Redox Signal 2011; 14(7): 1275-88.
[23]
Lunn JS, Sakowski SA, Hur J, Feldman EL. Stem cell technology for neurodegenerative diseases. Ann Neurol 2011; 70(3): 353-61.
[24]
O’Connor D, Boulis N. Gene therapy for neurodegenerative diseases. Trends Mol Med 2015; 21(8): 504-12.
[25]
Dantuma E, Merchant S, Sugaya K. Stem cells for the treatment of neurodegenerative diseases. Stem Cell Res Ther 2010; 1(5): 37.
[26]
Zhongling Feng, Gang Zhao, Lei Yu Neural stem cells and Alzheimer’s Disease: Challenges and hope. Am J Alzheimer’s Disease Dement 2008; 24(1): 52-7.
[27]
Winkler J. Human neural stem cells improve cognitive function of aged brain. Neuroreport 2001; 12(6): A33.
[28]
Kim J, Zaehres H, Wu G, et al. Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature 2008; 454(7204): 646-50.
[29]
Eminli S, Utikal J, Arnold K, Jaenisch R, Hochedlinger K. Reprogramming of neural progenitor cells into induced pluripotent stem cells in the absence of exogenous Sox2 expression. Stem Cells 2008; 26(10): 2467-74.
[30]
Imamura K, Inoue H. Research on neurodegenerative diseases using induced pluripotent stem cells. Psychogeriatrics 2012; 12(2): 115-9.
[31]
Murrell W, Wetzig A, Donnellan M, et al. Olfactory mucosa is a potential source for autologous stem cell therapy for Parkinson’s Disease. Stem Cells 2008; 26(8): 2183-92.
[32]
Nanou A, Azzouz M. Gene therapy for neurodegenerative diseases based on lentiviral vectors. Prog Brain Res 2009; 175: 187-200.
[33]
Matsuzaki Y, Oue M, Hirai H. Generation of a neurodegenerative disease mouse model using lentiviral vectors carrying an enhanced synapsin I promoter. J Neurosci Methods 2014; 223: 133-43.
[34]
Ramassamy C. Emerging role of polyphenolic compounds in the treatment of neurodegenerative diseases: A review of their intracellular targets. Eur J Pharmacol 2006; 545(1): 51-64.
[35]
Maiti P. Dietary curcumin: A potent natural polyphenol for neurodegenerative diseases therapy MOJ Anatomy Physiol 2015; 1(5).
[36]
Bacchus W, Aubel D, Fussenegger M. Biomedically relevant circuit-design strategies in mammalian synthetic biology. Mol Syst Biol 2014; 9(1): 691.
[37]
Ye H, Fussenegger M. Synthetic therapeutic gene circuits in mammalian cells. FEBS Lett 2014; 588(15): 2537-44.
[38]
Pham E, Mills E, Truong K. A synthetic photoactivated protein to generate local or global Ca2+ signals. Cell Chem Biol 2011; 18: 880-90.
[39]
Siuti P, Yazbek J, Lu T. Synthetic circuits integrating logic and memory in living cells. Nat Biotechnol 2013; 31(5): 448-52.
[40]
Grunberg R, Serrano L. Strategies for protein synthetic biology. Nucleic Acids Res 2010; 38(8): 2663-75.
[41]
Grunberg R, Ferrar T, van der Sloot A, Constante M, Serrano L. Building blocks for protein interaction devices. Nucleic Acids Res 2010; 38(8): 2645-62.
[42]
Yu K, Liu C, Kim B, Lee D. Synthetic fusion protein design and applications. Biotechnol Adv 2014; 33: 155-64.
[43]
Wu X, Sereno A, Huang F, et al. Protein design of IgG/TCR chimeras for the co-expression of Fab-like moieties within bispecific antibodies. MAbs 2015; 7(2): 364-76.
[44]
Cheng T, Roffler S. Membrane-tethered proteins for basic research, imaging, and therapy. Med Res Rev 2008; 28(6): 885-928.
[45]
Zhao X, Wang Y, Chen L, Aihara K. Protein domain annotation with predicted domain-domain interaction networks. Protein Pept Lett 2008; 15(5): 456-62.
[46]
Moad H, Pioszak A. Selective CGRP and adrenomedullin peptide binding by tethered RAMP-calcitonin receptor-like receptor extracellular domain fusion proteins. Protein Sci 2013; 22(12): 1775-85.
[47]
Schwerk C, Prasad J, Degenhardt K, et al. ASAP, a novel protein complex involved in RNA processing and apoptosis. Mol Cell Biol 2003; 23(8): 2981-90.
[48]
Huang K. Signaling properties of VEGF receptor-1 and -2 homo- and heterodimers. Int J Biochem Cell Biol 2001; 33(4): 315-24.
[49]
Mills E, Pham E, Truong K. Structure based design of a Ca2+-sensitive RhoA protein that controls cell morphology. Cell Ca 2010; 48: 195-201.
[50]
Howard P, Chia M, Del Rizzo S, Liu F, Pawson T. Redirecting tyrosine kinase signaling to an apoptotic caspase pathway through chimeric adaptor proteins. Proc Natl Acad Sci USA 2003; 100(20): 11267-72.
[51]
Strickland D, Moffat K, Sosnick T. Light-activated DNA binding in a designed allosteric protein. Proc Natl Acad Sci USA 2008; 105(31): 10709-14.
[52]
Bashor C, Helman N, Yan S, Lim W. using engineered scaffold interactions to reshape MAP kinase pathway signaling dynamics. Science 2008; 319(5869): 1539-43.
[53]
Khalil A, Collins J. Synthetic biology: Applications come of age. Nat Rev Genet 2010; 11(5): 367-79.
[54]
Trowbridge I. Signal-dependent membrane protein trafficking in the endocytic pathway. Annu Rev Cell Dev Biol 1993; 9(1): 129-61.
[55]
Bledi Y. PROCEED: A proteomic method for analysing plasma membrane proteins in living mammalian cells. Brief Funct Genomics Proteomics 2003; 2(3): 254-65.
[56]
Bonifacino J, Traub L. Signals for sorting of transmembrane proteins to endosomes and lysosomes. Annu Rev Biochem 2003; 72(1): 395-447.
[57]
Hegde R, Kang S. The concept of translocational regulation. J Cell Biol 2008; 182(2): 225-32.
[58]
Mellman I, Nelson W. Coordinated protein sorting, targeting and distribution in polarized cells. Nat Rev Mol Cell Biol 2008; 9(11): 833-45.
[59]
Martoglio B, Dobberstein B. Signal sequences: More than just greasy peptides. Trends Cell Biol 1998; 8(10): 410-5.
[60]
Hegde R, Bernstein H. The surprising complexity of signal sequences. Trends Biochem Sci 2006; 31(10): 563-71.
[61]
Bonifacino J, Lippincott-Schwartz J. Opinion: Coat proteins: Shaping membrane transport. Nat Rev Mol Cell Biol 2003; 4(5): 409-14.
[62]
Nikolovski N, Shliaha P, Gatto L, Dupree P, Lilley K. Label-free protein quantification for plant golgi protein localization and abundance. Plant Physiol 2014; 166(2): 1033-43.
[63]
Chang M, Mallet W, Mostov K, Brodsky F. Adaptor self-aggregation, adaptor-receptor recognition and binding of alpha-adaptin subunits to the plasma membrane contribute to recruitment of adaptor (AP2) components of clathrin-coated pits. EMBO J 1993; 12(5): 2169-80.
[64]
Nagaraj S, Wong SS, Truong K. Parts-based assembly of synthetic transmembrane proteins in mammalian cells. ACS Synth Biol 2012; 4(1): 111-7.
[65]
Yoneya T, Nishida R. TCP: A tool for designing chimera proteins based on the tertiary structure information. BMC Bioinformatics 2009; 10(1): 9.
[66]
Schott WJ, Galla M, Godinho T, Baum C, Schambach A. Viral and non-viral approaches for transient delivery of mrna and proteins. Curr Gene Ther 2011; 11(5): 382-98.
[67]
Lu Y, Yang J, Sega E. Issues related to targeted delivery of proteins and peptides. AAPS J 2006; 8(3): E466-78.
[68]
Bolhassani A, Jafarzade B, Mardani G. In vitro and in vivo delivery of therapeutic proteins using cell penetrating peptides. Peptides 2017; 87: 50-63.
[69]
Oller-Salvia B, Sánchez-Navarro M, Giralt E, Teixidó M. Blood-brain barrier shuttle peptides: An emerging paradigm for brain delivery. Chem Soc Rev 2016; 45(17): 4690-707.
[70]
Sellers D, Bergen J, Johnson R, et al. Targeted axonal import (TAxI) peptide delivers functional proteins into spinal cord motor neurons after peripheral administration. Proc Natl Acad Sci USA 2016; 113(9): 2514-9.
[71]
Kwon E, Skalak M, Lo Bu R, Bhatia S. Neuron-targeted nanoparticle for siRNA delivery to traumatic brain injuries. ACS Nano 2016; 10(8): 7926-33.
[72]
Clapham D. Calcium Signaling. Cell 2007; 131(6): 1047-58.
[73]
Pham E, Mills E, Truong K. A synthetic photoactivated protein to generate local or global Ca2+ signals. Chem Biol 2011; 18(7): 880-90.
[74]
Mills E, Pham E, Truong K. Structure based design of a Ca2+-sensitive RhoA protein that controls cell morphology. Cell Calcium 2010; 48(4): 195-201.
[75]
Faehling M. Essential role of calcium in vascular endothelial growth factor A-induced signaling: mechanism of the antiangiogenic effect of carboxyamidotriazole. FASEB J 2002; 16(13): 1805-7.
[76]
Zhang Z, Zhang L, Jiang Q, et al. VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest 2000; 106(7): 829-38.
[77]
Klemm J, Schreiber S, Crabtree G. Dimerization as a regulatory mechanism in signal transduction. Annu Rev Immunol 1998; 16(1): 569-92.
[78]
Dawson A, Lea E, Irvine R. Kinetic model of the inositol trisphosphate receptor that shows both steady-state and quantal patterns of Ca2+ release from intracellular stores. Biochem J 2003; 370: 621.
[79]
Ji X, Tordova M, O’Donnell R, et al. Structure and function of the xenobiotic substrate-binding site and location of a potential non-substrate-binding site in a slass π glutathione s-transferase. Biochem 1997; 36(32): 9690-702.
[80]
Rizzuto R, De Stefani D, Raffaello A, Mammucari C. Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol 2012; 13(9): 566-78.
[81]
Qudrat A, Mosabbir A, Truong K. Engineered proteins program mammalian cells to target inflammatory disease sites. Cell Chem Biol 2017; 24(6): 703-11.
[82]
Qudrat A, Truong K. Autonomous cell migration to CSF1 sources via a synthetic protein-based system. ACS Synth Biol 2017; 6(8): 1563-71.
[83]
Mosabbir A, Qudrat A, Truong K. Engineered cell migration to lesions linked to autoimmune disease. Biotechnol Bioeng 2018; 115(4): 1028-36.
[84]
Qudrat A, Wong J, Truong K. Engineering mammalian cells to seek senescence associated secretory phenotypes. J Cell Sci 2017; 130(18): 3116-23.
[85]
Qudrat A, Truong K. Antibody-based fusion proteins allow Ca2+ rewiring to most extracellular ligands. ACS Synth Biol 2018; 7(2): 531-9.
[86]
Mills E, Truong K. Ca2+-mediated synthetic biosystems offer protein design versatility, signal specificity and pathway rewiring. Cell Chem Biol 2011; 18: 1611-9.
[87]
Zimmer M. Green Fluorescent Protein (GFP): Applications, structure, and related photophysical behavior. Chem Rev 2002; 102(3): 759-82.
[88]
Hoffman R. Strategies for in vivo imaging using fluorescent proteins. J Cell Biochem 2017; 118(9): 2571-80.
[89]
Yang K, Sun K, Srinivasan KN, et al. Immune responses to T-cell epitopes of sars cov-n protein are enhanced by n immunization with a chimera of lysosome-associated membrane protein. Gene Ther 2009; 16(11): 1353-62.
[90]
Azab Belal M. Dash R, et al Enhanced prostate cancer gene transfer and therapy using a novel serotype chimera cancer terminator virus (Ad.5/3-CTV). J Cell Physiol 2014; 229(1): 34-43.
[91]
Dantuma N, Menéndez-Benito V, Verhoef L. The ubiquitin/proteasome system in neurodegenerative disease. Eur Neuropsychopharmacol 2006; 16: S183.

© 2024 Bentham Science Publishers | Privacy Policy