Molecular Neurobiology

, Volume 55, Issue 5, pp 4009–4029 | Cite as

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

  • Saima Zafar
  • Neelam Younas
  • Nadeem Sheikh
  • Waqas Tahir
  • Mohsin Shafiq
  • Matthias Schmitz
  • Isidre Ferrer
  • Olivier Andréoletti
  • Inga Zerr


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.


Cofilin Actin CJD MM1 VV2 Prion protein LIMK Rock APP SSH1 Microglia Cerebellum Cortex 



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

Compliance with Ethical Standards

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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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Saima Zafar
    • 1
  • Neelam Younas
    • 1
  • Nadeem Sheikh
    • 2
  • Waqas Tahir
    • 1
  • Mohsin Shafiq
    • 1
  • Matthias Schmitz
    • 1
  • Isidre Ferrer
    • 3
    • 4
  • Olivier Andréoletti
    • 5
  • Inga Zerr
    • 1
  1. 1.Department of Neurology, Clinical Dementia Center, and DZNEGeorg-August University, University Medical Center Goettingen (UMG)GoettingenGermany
  2. 2.Department of ZoologyUniversity of the PunjabLahorePakistan
  3. 3.Institute of NeuropathologyIDIBELL—University Hospital Bellvitge, University of BarcelonaHospitalet de LlobregatSpain
  4. 4.Network Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Institute Carlos III, Ministry of HealthMadridSpain
  5. 5.Institut National de la Recherche Agronomique/Ecole Nationale VétérinaireToulouseFrance

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