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Creutzfeldt-Jakob Disease Subtype-Specific Regional and Temporal Regulation of ADP Ribosylation Factor-1-Dependent Rho/MLC Pathway at Pre-Clinical Stage

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Abstract

Small GTPases of the Arf family mainly activate the formation of coated carrier vesicles. We showed that class-I Arf1 interacts specifically with full length GPI-anchored cellular prion protein (PrPC). Several recent reports have also demonstrated a missing link between the endoplasmic reticulum and the Golgi-complex role for proper folding, but the exact molecular mechanism is not yet fully understood. In the present study, we identified and characterized the interactive role of Arf1 during PrPC intracellular distribution under pathophysiological conditions. PrPC interaction with Arf1 was investigated in cortical primary neuronal cultures of PrPC wild type and knockout mice (PrP−/−). Arf1 and PrPC co-binding affinity was confirmed using reverse co-immunoprecipitation, co-localization affinity using confocal laser-scanning microscopy. Treatment with brefeldin-A modulated Arf1 expression and resulted in down-regulation and redistribution of PrPC into cytosolic region. In the pre-symptomatic stage of the disease, Arf1 expression was significantly downregulated in the frontal cortex in tg340 mice expressing about fourfold of human PrP-M129 with PrP null background that had been inoculated with human sCJD MM1 brain tissue homogenates (sCJD MM1 mice). In addition, the frontal cortex of CJD human brain demonstrated significant binding capacity of Arf1 protein using co-immunoprecipitation analysis. We also examined Arf1 expression in the brain of CJD patients with the subtypes MM1 and VV2 and found that it was regulated in a region-specific manner. In the frontal cortex, Arf1 expression was not significantly changed in either MM1 or VV2 subtype. Interestingly, Arf1 expression was significantly reduced in the cerebellum in both subtypes as compared to controls. Furthermore, we observed altered RhoA activity, which in turn affects myosin light-chain (MLC) phosphorylation and Arf1-dependent PI3K pathway. Together, our findings underscore a key early symptomatic role of Arf1 in neurodegeneration. Targeting the Arf/Rho/MLC signaling axis might be a promising strategy to uncover the missing link which probably influences disease progression and internal homeostasis of misfolded proteins.

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Acknowledgments

Special thanks to Dr Torres at CISA INIA who produced the tg340 mice.

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Authors and Affiliations

  1. Department of Neurology, Clinical Dementia Center and DZNE, Georg-August University, University Medical Center Goettingen (UMG), Robert-Koch-Str. 40, 37075, Goettingen, Germany

    Saima Zafar, Matthias Schmitz, Neelam Younus, Waqas Tahir, Mohsin Shafiq, Franc Llorens & Inga Zerr

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

    Isidre Ferrer

  3. CIBERNED (Network center for biomedical research of neurodegenerative diseases), Ministry of Health, Institute Carlos III, Madrid, Spain

    Isidre Ferrer

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

    Olivier Andéoletti

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  1. Saima Zafar
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  2. Matthias Schmitz
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  3. Neelam Younus
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  4. Waqas Tahir
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  9. Inga Zerr
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Correspondence to Saima Zafar.

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Author Summary

Prion diseases are fatal neurodegenerative diseases that affect a number of different species, including humans. A long pre-clinical phase of the disease lasting months to years is a basic characteristic of the prion diseases. During the disease replication stage, the affected individual does not show any signs of the disease. The clinical or symptomatic stage of the disease is much shorter than the pre-clinical stage. Variant CJD appears to not only be transmitted by eating contaminated beef but also by blood transfusions. In the latter cases, the blood donors had prion diseases in a pre-clinical stage and the prion disease was diagnosed at a later date. Given the potential for large numbers of people to have a clinically inapparent prion infection, it is critical for public health concerns that diagnostic tools be developed to detect the disease as early as possible. To address this need, we have developed a mouse model of prion disease to study the molecular pathways involved during disease progression. Targeting Arf/Rho/MLC signaling pathways might be a promising strategy to study the most likely cause of variant rate of disease progression and internal homeostasis of misfolded proteins.

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Zafar, S., Schmitz, M., Younus, N. et al. Creutzfeldt-Jakob Disease Subtype-Specific Regional and Temporal Regulation of ADP Ribosylation Factor-1-Dependent Rho/MLC Pathway at Pre-Clinical Stage. J Mol Neurosci 56, 329–348 (2015). https://doi.org/10.1007/s12031-015-0544-3

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