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Analysis of RNA Expression Profiles Identifies Dysregulated Vesicle Trafficking Pathways in Creutzfeldt-Jakob Disease

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Abstract

Functional genomics applied to the study of RNA expression profiles identified several abnormal molecular processes in experimental prion disease. However, only a few similar studies have been carried out to date in a naturally occurring human prion disease. To better characterize the transcriptional cascades associated with sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, we investigated the global gene expression profile in samples from the frontal cortex of 10 patients with sCJD and 10 non-neurological controls by microarray analysis. The comparison identified 333 highly differentially expressed genes (hDEGs) in sCJD. Functional enrichment Gene Ontology analysis revealed that hDEGs were mainly associated with synaptic transmission, including GABA (q value = 0.049) and glutamate (q value = 0.005) signaling, and the immune/inflammatory response. Furthermore, the analysis of cellular components performed on hDEGs showed a compromised regulation of vesicle-mediated transport with mainly up-regulated genes related to the endosome (q value = 0.01), lysosome (q value = 0.04), and extracellular exosome (q value < 0.01). A targeted analysis of the retromer core component VPS35 (vacuolar protein sorting-associated protein 35) showed a down-regulation of gene expression (p value= 0.006) and reduced brain protein levels (p value= 0.002). Taken together, these results confirm and expand previous microarray expression profile data in sCJD. Most significantly, they also demonstrate the involvement of the endosomal-lysosomal system. Since the latter is a common pathogenic pathway linking together diseases, such as Alzheimer’s and Parkinson’s, it might be the focus of future studies aimed to identify new therapeutic targets in neurodegenerative diseases.

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Availability of Data and Materials

Microarray data will be deposited in the GEO database. Other datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

Supported by EU Grant FP6, BNEII No LSHM-CT-2004-503039, the University of Bologna (Grant RFO) and the Gino Galletti Foundation.

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Author notes

  1. Sabina Capellari and Piero Parchi contributed equally to this work.

Authors and Affiliations

  1. IRCCS Istituto delle Scienze Neurologiche di Bologna, Ospedale Bellaria, 40139, Bologna, Italy

    Anna Bartoletti-Stella, Sabina Capellari & Piero Parchi

  2. Department of Biomedical and NeuroMotor Sciences, DIBINEM, University of Bologna, 40123, Bologna, Italy

    Patrizia Corrado, Nicola Mometto, Simone Baiardi & Sabina Capellari

  3. Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, Rayne Building, London, UK

    Pascal F. Durrenberger

  4. Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany

    Thomas Arzberger

  5. Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany

    Thomas Arzberger & Hans Kretzschmar

  6. Division of Brain Sciences, Imperial College London, London, UK

    Richard Reynolds

  7. Department of Experimental, Diagnostic and Specialty Medicine, DIMES, University of Bologna, 40138, Bologna, Italy

    Piero Parchi

Author notes

  1. Hans Kretzschmar is deceased. This paper is dedicated to his memory.

    • Hans Kretzschmar
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  1. Anna Bartoletti-Stella
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Contributions

A.B.S. designed and supervised whole transcriptome analysis, performed and supervised mRNA studies, analyzed, interpreted the data, and wrote the manuscript. P.C. RNA designed and supervised extraction experiments and critically reviewed the manuscript. N.M. analyzed and interpreted the data and critically reviewed the manuscript. S.B. analyzed and interpreted the data and critically reviewed the manuscript. P.F.D. and R.R. designed and supervised the transcriptome analysis and critically reviewed the manuscript. T.A. selected and prepared the samples and critically reviewed the manuscript. H.K. participated in designing the project and provided some samples. S.C. designed and supervised the study and wrote the manuscript. P.P. collected and selected the brain samples, performed all histopathological analysis, supervised the overall study, and wrote the manuscript.

Corresponding authors

Correspondence to Sabina Capellari or Piero Parchi.

Ethics declarations

The protocol of the study was approved by the Local Ethics Committee.

Conflict of Interest

The authors declare that they have no competing interests.

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Bartoletti-Stella, A., Corrado, P., Mometto, N. et al. Analysis of RNA Expression Profiles Identifies Dysregulated Vesicle Trafficking Pathways in Creutzfeldt-Jakob Disease. Mol Neurobiol 56, 5009–5024 (2019). https://doi.org/10.1007/s12035-018-1421-1

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  • DOI: https://doi.org/10.1007/s12035-018-1421-1

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