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

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Abstract

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.

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Abbreviations

sCJD:

Sporadic Creutzfeldt–Jakob disease

PrPC :

Cellular prion protein

PrPSc :

Scrapie form of prion proteins

2DE:

Two-dimensional gel electrophoresis

OS:

Oxidative stress

CSF:

Cerebrospinal fluid

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Acknowledgements

This work was supported by a grant from Helmholtz-Alberta Initiative-Infectious Diseases Research (HAI-IDR) and APRI-Human prions—distinguishing sporadic from familial forms via structure and function as well as from the DZNE clinical project (Helmholtz). The study was performed within the recently established Clinical Dementia Center at the University Medical Hospital Göttingen and was partly supported by grants from the EU Joint Program Neurodegenerative Disease Research (JPND-DEMTEST) (Biomarker based diagnosis of rapid progressive dementias-optimization of diagnostic protocols, 01ED1201A). We also pay our special thanks to Dr. André Fischer (DZNE, Goettingen) and Dr. Stefan Bonn (DZNE, Goettingen) for sharing their lab facilities, Dr. Christine Stadelmann-Nessler (UMG, Goettingen) for providing hemeoxygenase 1 primary antibody and Dr. Hassan Dihazi (UMG, Goettingen) for peroxiredoxin 6 primary antibody.

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Authors and Affiliations

  1. Department of Neurology, University Medical Center Goettingen (UMG) and German Center for Neurodegenerative Diseases (DZNE) Goettingen, Robert-Koch-Str., 40, 37075, Goettingen, Germany

    Waqas Tahir, Saima Zafar, Franc Llorens, Amandeep Singh Arora, Katrin Thüne, Matthias Schmitz, Nadine Gotzmann & Inga Zerr

  2. Institute of Neuropathology, University Medical Center Goettingen (UMG), Robert-Koch-Str. 40, 37075, Goettingen, Germany

    Niels Kruse & Brit Mollenhauer

  3. Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Carretera de Algete a El Casar Km. 8,1 S/N, 28130, Valdeolmos, Madrid, Spain

    Juan Maria Torres

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

    Olivier Andréoletti

  5. Institute of Neuropathology, Hospitalet de Llobregat, IDIBELL-University Hospital Bellvitge, University of Barcelona, Barcelona, Spain

    Isidre Ferrer

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

    Isidre Ferrer

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  1. Waqas Tahir
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Correspondence to Saima Zafar.

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Supplementary Fig. 1: Four silver stained 2DE gels corresponding to four samples in each biological group (Control, MM1 and VV2).Supplementary Fig. 2: Characterization of samples and methodology used for proteomics: (A) Western blot analysis for total PrP protein expression in cerebellum from MM1 (n = 4) and VV2 (n = 4) subtypes of sCJD along with their age-matched NDCs (n = 4) by using anti-PrP (SAF70) antibody is shown. Densitometeric analysis showed an increase of total PrP levels both in MM1 and VV2 subtypes as already reported before. GAPDH was used as a loading control. (B) Analysis for proteinase K (PK) resistant pathogenic PrPres from cerebellum in MM1 and VV2 subtypes of sCJD was performed by PK digestion of samples from MM1 (n = 4) and VV2 (n = 4) subtypes of sCJD along with age-matched NDCs (n = 4) from cerebellum of brain with 2.5 μg/ml of PK followed by separation on SDS-PAGE gel. Western blotting was performed by using anti-PrP (SAF70) antibody. Densitometeric analysis showed the presence of PK resistant PrP: PrPres levels both in MM1 and VV2 subtypes as compared to age-matched NDCs as already reported before. “E” is for empty well which was kept intentionally empty to avoid an overflow of samples between two adjacent wells. (C) SOD1 was identified by MS/ MS in protein spot 801 whose spot intensity was significantly increased in MM1 subtype. SOD1 is a protein which is already reported to be increased in MM1 and VV2 subtypes of sCJD. In this study, qPCR results showed a significant increase in mRNA expression of SOD1 in both MM1 (n = 15) and VV2 (n = 10) as compared with age matched NDC (n = 15) samples. Western blot results showed a significant increase in protein expression of SOD1 in both MM1 (n = 4) and VV2 (n = 4) as compared with age matched NDC (n = 4) samples. Statistical significance was calculated with one way ANOVA followed by Turkey post test to compare all pairs of columns. *p < 0.05, **p < 0.005, ***p < 0.001. These results of total PrP expression, PKres PrP expression and SOD1 expressional alteration in both MM1 and VV2 subtypes indicated the well characterization of samples, method of quantification of protein spots on 2DE gels with Delta2D DECODON software and MS/MS method of protein identification in this study.Supplementary Fig. 3: Regulation of spots used in validation of proteomics findings after mass-spectrometry.Supplementary Table 1: Primary Antibodies usedSupplementary Table 2: Secondary Antibodies usedSupplementary Table 3: Oligonucleotides (probes) used foqPCRsSupplementary Table 4: Kits and commercial buffers used (DOCX 605 kb)

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Tahir, W., Zafar, S., Llorens, F. et al. Molecular Alterations in the Cerebellum of Sporadic Creutzfeldt–Jakob Disease Subtypes with DJ-1 as a Key Regulator of Oxidative Stress. Mol Neurobiol 55, 517–537 (2018). https://doi.org/10.1007/s12035-016-0294-4

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