Molecular Alterations in the Cerebellum of Sporadic Creutzfeldt-Jakob Disease Subtypes with DJ-1 as a Key Regulator of Oxidative Stress

Mol Neurobiol. 2018 Jan;55(1):517-537. doi: 10.1007/s12035-016-0294-4. Epub 2016 Dec 14.


Cerebellar damage and granular and Purkinje cell loss in sporadic Creutzfeldt-Jakob disease (sCJD) highlight a critical involvement of the cerebellum during symptomatic progression of the disease. In this project, global proteomic alterations in the cerebellum of brain from the two most prevalent subtypes (MM1 and VV2) of sCJD were studied. Two-dimensional gel electrophoresis (2DE) coupled mass spectrometric identification revealed 40 proteins in MM1 and 43 proteins in VV2 subtype to be differentially expressed. Of those, 12 proteins showed common differential expression in their expression between two subtypes. Differentially expressed proteins mainly belonged to (i) cell cycle, gene expression and cell death; (ii) cellular stress response/oxidative stress (OS) and (iii) signal transduction and synaptic functions, related molecular functions. We verified 10 differentially expressed proteins at transcriptional and translational level as well. Interestingly, protein deglycase DJ-1 (an antioxidative protein) showed an increase in its messenger RNA (mRNA) expression in both MM1 and VV2 subtypes but protein expression only in VV2 subtype in cerebellum of sCJD patients. Nuclear translocalization of DJ-1 confirmed its expressional alteration due to OS in sCJD. Downstream experiments showed the activation of nuclear factor erythroid-2 related factor 2 (Nrf2)/antioxidative response element (ARE) pathway. DJ-1 protein concentration was significantly increased during the clinical phase in cerebrospinal fluid of sCJD patients and also at presymptomatic and symptomatic stages in cerebellum of humanized PrP transgenic mice inoculated with sCJD (MM1 and VV2) brain. These results suggest the implication of oxidative stress during the pathophysiology of sCJD.

Keywords: Antioxidative response elements; Mass spectrometry; Parkinson disease protein 7/protein deglycase DJ-1; Sporadic Creutzfeldt–Jakob disease; Two-dimensional gel electrophoresis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebellum / metabolism*
  • Cerebellum / pathology*
  • Creutzfeldt-Jakob Syndrome / metabolism*
  • Creutzfeldt-Jakob Syndrome / pathology*
  • Creutzfeldt-Jakob Syndrome / physiopathology
  • Disease Progression
  • Humans
  • Mice, Knockout
  • Oxidative Stress*
  • Protein Deglycase DJ-1 / metabolism*
  • Proteomics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reproducibility of Results
  • Signal Transduction
  • Software
  • Tandem Mass Spectrometry


  • RNA, Messenger
  • PARK7 protein, human
  • PARK7 protein, mouse
  • Protein Deglycase DJ-1

Supplementary concepts

  • Creutzfeldt-Jakob Disease, Sporadic