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

Mol Neurobiol. 2018 May;55(5):4009-4029. doi: 10.1007/s12035-017-0589-0. Epub 2017 Jun 1.


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.

Keywords: APP; Actin; CJD; Cerebellum; Cofilin; Cortex; LIMK; MM1; Microglia; Prion protein; Rock; SSH1; VV2.

MeSH terms

  • Actins / metabolism
  • Aged
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Calcineurin / metabolism
  • Calcium-Binding Proteins / metabolism
  • Cell Survival
  • Cells, Cultured
  • Cofilin 1 / metabolism
  • Creutzfeldt-Jakob Syndrome / pathology*
  • Cytoskeleton / metabolism*
  • Disease Progression*
  • Female
  • Gene Silencing
  • Humans
  • Lim Kinases / metabolism
  • Male
  • Mice, Transgenic
  • Microfilament Proteins / metabolism
  • Microglia / metabolism
  • Middle Aged
  • Neurons / metabolism
  • Phosphoprotein Phosphatases / metabolism
  • Phosphorylation
  • PrPC Proteins / metabolism
  • Protein Binding
  • RNA, Small Interfering / metabolism
  • Risk Factors
  • rho-Associated Kinases / metabolism


  • Actins
  • Aif1 protein, mouse
  • Amyloid beta-Peptides
  • Calcium-Binding Proteins
  • Cofilin 1
  • Microfilament Proteins
  • PrPC Proteins
  • RNA, Small Interfering
  • LIMK1 protein, human
  • Lim Kinases
  • ROCK2 protein, human
  • rho-Associated Kinases
  • Calcineurin
  • Phosphoprotein Phosphatases
  • SSH1 protein, human

Supplementary concepts

  • Creutzfeldt-Jakob Disease, Sporadic