Role of the cellular prion protein in the cellular internalization and the Tau-mediated toxicity

by Anna-Lisa Fischer
Doctoral thesis
Date of Examination:2024-09-20
Date of issue:2024-11-15
Advisor:Prof. Dr. Inga Zerr
Referee:Prof. Dr. André Fischer
Referee:Prof. Dr. Christine Stadelmann-Nessler
Referee:Prof. Dr. Michael Werner Sereda
Referee:Prof. Dr. Oliver Wirths
Referee:Prof. Dr. Niels Focke
Persistent Address: http://dx.doi.org/10.53846/goediss-10875

 

 

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Abstract

English

Tauopathies represent a group of neurodegenerative disorders characterized by the accumulation of Tau within the brain, leading to neuronal dysfunction and death. These diseases are classified into 3R tauopathies, 4R tauopathies, and combined 3R/4R tauopathies based on the predominant Tau isoform deposited. The aggregation of Tau disrupts cellular function, and their toxic oligomerization and fibrillization are driven by genetic mutations, Post-tranlational modifications (PTMs), or spontaneous aggregation. There is an evidence suggesting that misfolded Tau can propagate between cells in a prion-like mechanism, involving the cellular prion protein (PrPC) as a receptor. This dissertation explores the role of PrPC in the internalization of Tau protein, which is implicated in various neurodegenerative disorders such as tauopathies. I found a strong and stable interaction between PrPC and various Tau isoforms via surface plasmon resonance (SPR) analysis, which revealed that PrPC exhibits the highest binding affinity to Tau 1N4R. Moreover, I found out that Tau and PrPC are colocalized in the membrane of SH-SY5Y cells. Additionally, cellular uptake experiments using SH-SY5Y cells with varying levels of PrPC expression demonstrated significantly higher internalization of Tau 0N4R in PrPC -overexpressing cells. This was further confirmed in primary neuronal cells with reduced PrPC expression, where all Tau isoforms were markedly decreased. Proteomic analysis via mass spectrometry identified significant protein expression changes in SHPrP cells treated with Tau 0N4R, highlighting pathways involved in apoptosis and neurodegeneration. Key findings include the upregulation of caveolin-1 (Cav1). These observations were further confirmed using a Cav1 knockout (CavKO) model. CavKO cells showed reduced uptake of various Tau isoforms compared to WT cells. Moreover, direct interactions between different Tau isoforms and Cav1 were identified through SPR analysis. This underscores the crucial role of Cav1 in PrPC -mediated uptake of Tau and provides new insights into the mechanism underlying tauopathies. In summary, this dissertation provides critical insights into the role of PrPC as a receptor in tauopathies, highlighting its central role in Tau protein uptake and the involvement of Cav1. The interaction between PrPC and Tau at the membrane level and within caveolae underscores a novel mechanism in the pathogenesis of tauopathies. These findings enhance insights into potential therapeutic strategies targeting PrPC -Tau interactions to mitigate the progression of neurodegenerative diseases.
Keywords: Tauopathies; Prion; cellular prion protein; PrPC; Tau; caveolin-1; Protein interaction
Schlagwörter: Tauopathie; PrPC; Prion; Cellular Prion Protein; Tau; Caveolin-1