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Cytoskeleton-Associated Risk Modifiers Involved in Early and Rapid Progression of Sporadic Creutzfeldt-Jakob Disease

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Abstract

A high priority in the prion field is to identify pre-symptomatic events and associated profile of molecular changes. In this study, we demonstrate the pre-symptomatic dysregulation of cytoskeleton assembly and its associated cofilin-1 pathway in strain and brain region-specific manners in MM1 and VV2 subtype-specific Creutzfeldt-Jakob disease at clinical and pre-clinical stage. At physiological level, PrPC interaction with cofilin-1 and phosphorylated form of cofilin (p-cofilin(Ser3)) was investigated in primary cultures of mouse cortex neurons (PCNs) of PrPC wild-type and knockout mice (PrP−/−). Short-interfering RNA downregulation of active form of cofilin-1 resulted in the redistribution/downregulation of PrPC, increase of activated form of microglia, accumulation of dense form of F-actin, and upregulation of p-cofilin(Ser3). This upregulated p-cofilin(Ser3) showed redistribution of expression predominantly in the activated form of microglia in PCNs. At pathological level, cofilin-1 expression was significantly altered in cortex and cerebellum in both humans and mice at pre-clinical stage and at early symptomatic clinical stage of the disease. Further, to better understand the possible mechanism of dysregulation of cofilin-1, we also demonstrated alterations in upstream regulators; LIM kinase isoform 1 (LIMK1), slingshot phosphatase isoform 1 (SSH1), RhoA-associated kinase (Rock2), and amyloid precursor protein (APP) in sporadic Creutzfeldt-Jakob disease MM1 mice and in human MM1 and VV2 frontal cortex and cerebellum samples. In conclusion, our findings demonstrated for the first time a key pre-clinical response of cofilin-1 and the associated pathway in prion disease.

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References

  1. Tschampa HJ, Kallenberg K, Kretzschmar HA, Meissner B, Knauth M, Urbach H, Zerr I (2007) Pattern of cortical changes in sporadic Creutzfeldt-Jakob disease. Am J Neuroradiol 28:1114–1118

    Article  CAS  PubMed  Google Scholar 

  2. Bishop MT, Will RG, Manson JC (2010) Defining sporadic Creutzfeldt-Jakob disease strains and their transmission properties. Proc Natl Acad Sci 107:12005–12010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, Zerr I, Budka H et al (1999) Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 46:224–233

    Article  CAS  PubMed  Google Scholar 

  4. Parchi P, Strammiello R, Notari S, Giese A, Langeveld JP, Ladogana A, Zerr I, Roncaroli F et al (2009) Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification. Acta Neuropathol 118:659–671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ferrer I, Puig B, Blanco R, Marti E (2000) Prion protein deposition and abnormal synaptic protein expression in the cerebellum in Creutzfeldt-Jakob disease. Neuroscience 97:715–726

    Article  CAS  PubMed  Google Scholar 

  6. Jeffrey M, Halliday WG, Bell J, Johnston AR, Mac Leod NK, Ingham C, Sayers AR, Brown DA et al (2000) Synapse loss associated with abnormal PrP precedes neuronal degeneration in the scrapie-infected murine hippocampus. Neuropathol Appl Neurobiol 26:41–54

    Article  CAS  PubMed  Google Scholar 

  7. Jeffrey M, McGovern G, Sisó S, González L (2011) Cellular and sub-cellular pathology of animal prion diseases: relationship between morphological changes, accumulation of abnormal prion protein and clinical disease. Acta Neuropathol 121:113–134

    Article  CAS  PubMed  Google Scholar 

  8. Loubet D, Dakowski C, Pietri M, Pradines E, Bernard S, Callebert J, Ardila-Osorio H, Mouillet-Richard S et al (2012) Neuritogenesis: the prion protein controls beta1 integrin signaling activity. FASEB J 26:678–690

    Article  CAS  PubMed  Google Scholar 

  9. Zafar S, Younas N, Correia S, Shafiq M, Tahir W, Schmitz M, Ferrer I, Andreoletti O et al (2016) Strain-specific altered regulatory response of Rab7a and Tau in Creutzfeldt-Jakob disease and Alzheimer’s disease. Mol Neurobiol

  10. Eiseler T, Hausser A, De Kimpe L, Van Lint J, Pfizenmaier K (2010) Protein kinase D controls actin polymerization and cell motility through phosphorylation of cortactin. J Biol Chem 285:18672–18683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Munnamalai V, Weaver CJ, Weisheit CE, Venkatraman P, Agim ZS, Quinn MT, Suter DM (2014) Bidirectional interactions between NOX2-type NADPH oxidase and the F-actin cytoskeleton in neuronal growth cones. J Neurochemn/a

  12. Yamada H, Abe T, Satoh A, Okazaki N, Tago S, Kobayashi K, Yoshida Y, Oda Y et al (2013) Stabilization of actin bundles by a dynamin 1/cortactin ring complex is necessary for growth cone filopodia. J Neurosci 33:4514–4526

    Article  CAS  PubMed  Google Scholar 

  13. Bosch M, Castro J, Saneyoshi T, Matsuno H, Sur M, Hayashi Y (2014) Structural and molecular remodeling of dendritic spine substructures during long-term potentiation. Neuron Cell Press 82:444–459

    CAS  Google Scholar 

  14. Okamoto K, Nagai T, Miyawaki A, Hayashi Y (2004) Rapid and persistent modulation of actin dynamics regulates postsynaptic reorganization underlying bidirectional plasticity. Nat Neurosci 7:1104–1112

    Article  CAS  PubMed  Google Scholar 

  15. Schubert V, Dotti CG (2007) Transmitting on actin: synaptic control of dendritic architecture. J Cell Sci 120:205–212

    Article  CAS  PubMed  Google Scholar 

  16. Sekino Y, Kojima N, Shirao T (2007) Role of actin cytoskeleton in dendritic spine morphogenesis. Neurochem Int 51:92–104

    Article  CAS  PubMed  Google Scholar 

  17. Star EN, Kwiatkowski DJ, Murthy VN (2002) Rapid turnover of actin in dendritic spines and its regulation by activity. Nat Neurosci 5:239–246

    Article  CAS  PubMed  Google Scholar 

  18. Bravo-Cordero JJ, Magalhaes MA, Eddy RJ, Hodgson L, Condeelis J (2013) Functions of cofilin in cell locomotion and invasion. Nat Rev Mol Cell Biol 14:405–415

    Article  CAS  PubMed  Google Scholar 

  19. Hagedorn EJ, Kelley LC, Naegeli KM, Wang Z, Chi Q, Sherwood DR (2014) ADF/cofilin promotes invadopodial membrane recycling during cell invasion in vivo. J Cell Biol 204:1209–1218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Vitriol EA, Wise AL, Berginski ME, Bamburg JR, Zheng JQ (2013) Instantaneous inactivation of cofilin reveals its function of F-actin disassembly in lamellipodia. Mol Biol Cell 24:2238–2247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kim T, Vidal GS, Djurisic M, William CM, Birnbaum ME, Garcia KC, Hyman BT, Shatz CJ (2013) Human LilrB2 is a beta-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer’s model. Science 341:1399–1404

  22. Bellenchi GC, Gurniak CB, Perlas E, Middei S, Ammassari-Teule M, Witke W (n.d.)

  23. Goodson M, Rust MB, Witke W, Bannerman D, Mott R, Ponting CP, Flint J (2012) Cofilin-1: a modulator of anxiety in mice. PLoS Genet 8:e1002970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gu J, Lee CW, Fan Y, Komlos D, Tang X, Sun C, Yu K, Hartzell HC et al (2010) ADF/cofilin-mediated actin dynamics regulate AMPA receptor trafficking during synaptic plasticity. Nat Neurosci 13:1208–1215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Rust MB, Gurniak CB, Renner M, Vara H, Morando L, Gorlich A, Sassoe-Pognetto M, Banchaabouchi MA et al (2010) Learning, AMPA receptor mobility and synaptic plasticity depend on n-cofilin-mediated actin dynamics. EMBO J 29:1889–1902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Van Troys M, Huyck L, Leyman S, Dhaese S, Vandekerkhove Jl, Ampe C (2008) Ins and outs of ADF/cofilin activity and regulation. Eur J Cell Biol

  27. Gu H, Yu SP, Gutekunst CA, Gross RE, Wei L (2013) Inhibition of the Rho signaling pathway improves neurite outgrowth and neuronal differentiation of mouse neural stem cells. Int J Physiol Pathophysiol Pharmacol 5:11–20

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Huang TY, Minamide LS, Bamburg JR, Bokoch GM (2008) Chronophin mediates an ATP-sensing mechanism for cofilin dephosphorylation and neuronal cofilin-actin rod formation. Dev Cell 15:691–703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nishita M, Tomizawa C, Yamamoto M, Horita Y, Ohashi K, Mizuno K (2005) Spatial and temporal regulation of cofilin activity by LIM kinase and Slingshot is critical for directional cell migration. J Cell Biol 171:349–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mizuno K (2013) Signaling mechanisms and functional roles of cofilin phosphorylation and dephosphorylation. Cell Signal 25:457–469

    Article  CAS  PubMed  Google Scholar 

  31. Kligys K, Yao J, Yu D, Jones JCR (2009) 14-3-3 zeta/tau heterodimers regulate Slingshot activity in migrating keratinocytes. Biochem Biophys Res Commun 383:450–454

  32. Ladogana A, Sanchez-Juan P, Mitrova E, Green A, Cuadrado-Corrales N, Sanchez-Valle R, Koscova S, Aguzzi A et al (2009) Cerebrospinal fluid biomarkers in human genetic transmissible spongiform encephalopathiesa. J Neurol 256:1620–1628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schmitz M, Ebert E, Stoeck K, Karch A, Collins S, Calero M, Sklaviadis T, Laplanche JL et al (2015) Validation of 14-3-3 protein as a marker in sporadic Creutzfeldt-Jakob disease diagnostic. Mol Neurobiol

  34. Zerr I, Bodemer M, Weber T (1997) The 14-3-3 brain protein and transmissible spongiform encephalopathy. N Engl J Med 336:874–875

    CAS  PubMed  Google Scholar 

  35. Llorens F, Ansoleaga B, Garcia-Esparcia P, Zafar S, Grau-Rivera O, Lopez-Gonzalez I, Blanco R, Carmona M et al (2013) PrP mRNA and protein expression in brain and PrP(c) in CSF in Creutzfeldt-Jakob disease MM1 and VV2. Prion 7:383–393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zafar S, Schmitz M, Younus N, Tahir W, Shafiq M, Llorens F, Ferrer I, Andeoletti O et al (2015) Creutzfeldt-Jakob disease subtype-specific regional and temporal regulation of ADP ribosylation factor-1-dependent rho/MLC pathway at pre-clinical stage. J Mol Neurosci 56:329–348

    Article  CAS  PubMed  Google Scholar 

  37. Padilla D, Beringue V, Espinosa JC, Andreoletti O, Jaumain E, Reine F, Herzog L, Gutierrez-Adan A et al (2011) Sheep and goat BSE propagate more efficiently than cattle BSE in human PrP transgenic mice. PLoS Pathog 7:e1001319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Carimalo J, Cronier S, Petit G, Peyrin JM, Boukhtouche F, Arbez N, Lemaigre-Dubreuil Y, Brugg B et al (2005) Activation of the JNK-c-Jun pathway during the early phase of neuronal apoptosis induced by PrP106-126 and prion infection. Eur J Neurosci 21:2311–2319

    Article  CAS  PubMed  Google Scholar 

  39. Bueler H, Fischer M, Lang Y, Bluethmann H, Lipp HP, DeArmond SJ, Prusiner SB, Aguet M et al (1992) Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356:577–582

    Article  CAS  PubMed  Google Scholar 

  40. Kawamoto JC, Barrett JN (1986) Cryopreservation of primary neurons for tissue culture. Brain Res 384:84–93

    Article  CAS  PubMed  Google Scholar 

  41. Knusel B, Michel PP, Schwaber JS, Hefti F (1990) Selective and nonselective stimulation of central cholinergic and dopaminergic development in vitro by nerve growth factor, basic fibroblast growth factor, epidermal growth factor, insulin and the insulin-like growth factors I and II. J Neurosci 10:558–570

    Article  CAS  PubMed  Google Scholar 

  42. Hotulainen P, Paunola E, Vartiainen MK, Lappalainen P (2005) Actin-depolymerizing factor and cofilin-1 play overlapping roles in promoting rapid F-actin depolymerization in mammalian nonmuscle cells. Mol Biol Cell 16:649–664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S (2004) Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431:805–810

    Article  CAS  PubMed  Google Scholar 

  44. Zafar S, Asif AR, Ramljak S, Tahir W, Schmitz M, Zerr I (2014) Anchorless 23-230 PrP(C) interactomics for elucidation of PrP(C) protective role. Mol Neurobiol 49:1385–1399

    Article  CAS  PubMed  Google Scholar 

  45. Cory AH, Owen TC, Barltrop JA, Cory JG (1991) Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture. Cancer Commun 3:207–212

    Article  CAS  PubMed  Google Scholar 

  46. Zafar S, von Ahsen N, Oellerich M, Zerr I, Schulz-Schaeffer WJ, Armstrong VW, Asif AR (2011) Proteomics approach to identify the interacting partners of cellular prion protein and characterization of Rab7a interaction in neuronal cells. J Proteome Res 10:3123–3135

    Article  CAS  PubMed  Google Scholar 

  47. Giorgi A, Di FL, Principe S, Mignogna G, Sennels L, Mancone C, Alonzi T, Sbriccoli M et al (2009) Proteomic profiling of PrP27-30-enriched preparations extracted from the brain of hamsters with experimental scrapie. Proteomics 9:3802–3814

    Article  CAS  PubMed  Google Scholar 

  48. Nebl G, Meuer SC, Samstag Y (1996) Dephosphorylation of serine 3 regulates nuclear translocation of cofilin. J Biol Chem 271(42):26276–26280

  49. Gurniak CB, Perlas E, Witke W (2005) The actin depolymerizing factor n-cofilin is essential for neural tube morphogenesis and neural crest cell migration. Dev Biol 278:231–241

    Article  CAS  PubMed  Google Scholar 

  50. Giese A, Brown DR, Groschup MH, Feldmann C, Haist I, Kretzschmar HA (1998) Role of microglia in neuronal cell death in prion disease. Brain Pathol 8:449–457

    Article  CAS  PubMed  Google Scholar 

  51. Llorens F, Lopez-Gonzalez I, Thune K, Carmona M, Zafar S, Andreoletti O, Zerr I, Ferrer I (2014) Subtype and regional-specific neuroinflammation in sporadic Creutzfeldt-Jakob disease. Front Aging Neurosci 6:198

    Article  PubMed  PubMed Central  Google Scholar 

  52. Minamide LS, Striegl AM, Boyle JA, Meberg PJ, Bamburg JR (2000) Neurodegenerative stimuli induce persistent ADF/cofilin-actin rods that disrupt distal neurite function. Nat Cell Biol 2:628–636

    Article  CAS  PubMed  Google Scholar 

  53. Rahman T, Davies DS, Tannenberg RK, Fok S, Shepherd C, Dodd PR, Cullen KM, Goldsbury C (2014a) Cofilin rods and aggregates concur with tau pathology and the development of Alzheimer’s disease. J Alzheimers Dis 42:1443–1460

    CAS  PubMed  Google Scholar 

  54. Woo JA, Zhao X, Khan H, Penn C, Wang X, Joly-Amado A, Weeber E, Morgan D et al (2015) Slingshot-cofilin activation mediates mitochondrial and synaptic dysfunction via Abeta ligation to beta1-integrin conformers. Cell Death Differ 22:921–934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bernstein BW, Bamburg JR (2010) ADF/cofilin: a functional node in cell biology. Trends Cell Biol 20:187–195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Liu L, Li J, Zhang L, Zhang F, Zhang R, Chen X, Brakebusch C, Wang Z et al (2015) Cofilin phosphorylation is elevated after F-actin disassembly induced by Rac1 depletion. Biofactors 41:352–359

    Article  CAS  PubMed  Google Scholar 

  57. Cottrell JR, Levenson JM, Kim SH, Gibson HE, Richardson KA, Sivula M, Li B, Ashford CJ et al (2013) Working memory impairment in calcineurin knock-out mice is associated with alterations in synaptic vesicle cycling and disruption of high-frequency synaptic and network activity in prefrontal cortex. J Neurosci 33:10938–10949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zeng H, Chattarji S, Barbarosie M, Rondi-Reig L, Philpot BD, Miyakawa T, Bear MF, Tonegawa S (2001) Forebrain-specific calcineurin knockout selectively impairs bidirectional synaptic plasticity and working/episodic-like memory. Cell 107:617–629

    Article  CAS  PubMed  Google Scholar 

  59. Mukherjee A, Soto C (2011) Role of calcineurin in neurodegeneration produced by misfolded proteins and endoplasmic reticulum stress. Curr Opin Cell Biol 23:223–230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gohla A, Bokoch GM (2002) 14-3-3 regulates actin dynamics by stabilizing phosphorylated cofilin. Curr Biol 12:1704–1710

    Article  CAS  PubMed  Google Scholar 

  61. Palmer KJ, Watson P, Stephens DJ (2005) The role of microtubules in transport between the endoplasmic reticulum and Golgi apparatus in mammalian cells. Biochem Soc Symp 1-13.

  62. Striebel JF, Race B, Carroll JA, Phillips K, Chesebro B (2016) Knockout of fractalkine receptor, Cx3cr1, does not alter disease or microglial activation in prion-infected mice. J Gen Virol

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Acknowledgements

We give special thanks to Dr. Torres at CISA INIA who produced the tg340 mice.

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  1. Saima Zafar and Neelam Younas have equal contributions.

Authors and Affiliations

  1. Department of Neurology, Clinical Dementia Center, and DZNE, Georg-August University, University Medical Center Goettingen (UMG), Robert-Koch-Str. 40, 37075, Goettingen, Germany

    Saima Zafar, Neelam Younas, Waqas Tahir, Mohsin Shafiq, Matthias Schmitz & Inga Zerr

  2. Department of Zoology, University of the Punjab, Lahore, Pakistan

    Nadeem Sheikh

  3. Institute of Neuropathology, IDIBELL—University Hospital Bellvitge, University of Barcelona, Hospitalet de Llobregat, Spain

    Isidre Ferrer

  4. Network Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Institute Carlos III, Ministry of Health, Madrid, Spain

    Isidre Ferrer

  5. Institut National de la Recherche Agronomique/Ecole Nationale Vétérinaire, Toulouse, France

    Olivier Andréoletti

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  1. Saima Zafar
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Correspondence to Saima Zafar.

Ethics declarations

Human samples from the Institute of Neuropathology Brain Bank (HUB-ICO-IDIBELL Biobank) and Biobank of Hospital Clinic-IDIBAPS were obtained following the Spanish legislation (Ley de la Investigación Biomédica 2013 and Real DecretoBiobancos 2014) and the approval of the local ethics committees.

All animal experiments were performed in accordance with the ethical standard set by Regierungspräsidium Tübingen (Regional Council) Experimental No. FLI 231/07 file reference number 35/9185.81-2. All animal experiments have been performed in compliance with the institutional and French national guidelines, in accordance with the European Community Council Directive 86/609/EEC. The experimental protocol was approved by the INRA Toulouse/ENVT ethics committee.

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Significance Statement

In prion field, a high demand is arising to uncover pre-clinical events and the alteration of associated pathway as the clinical stage is much squatter than pre-clinical stage. For public health concern, early diagnosis is a big need as the disease can be transmitted by blood. So, if the blood donors had prion disease in a pre-clinical stage, and the prion disease was diagnosed at a later date, this could be a risk for public health and a concern to develop diagnostic tools by studying early pre-clinical molecular pathways. To address this need, targeting cofilin-1 activity in LIMK-APP-SSH1 signaling pathways might be a promising strategy to study the most likely disease progression and the internal homeostasis of misfolded proteins.

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Zafar, S., Younas, N., Sheikh, N. et al. Cytoskeleton-Associated Risk Modifiers Involved in Early and Rapid Progression of Sporadic Creutzfeldt-Jakob Disease. Mol Neurobiol 55, 4009–4029 (2018). https://doi.org/10.1007/s12035-017-0589-0

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