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Titel: Investigation of the therapeutic potential of the neuroprotective prion protein N1-fragment in cellular and mouse models of Alzheimers and prion disease
Sonstige Titel: Untersuchung des therapeutischen Potentials von neuroprotektivem Prion Protein N1-Fragment im Zell- und Mausmodell von Alzheimer und Prionen Erkrankungen
Sprache: Englisch
Autor*in: Mohammadi, Behnam
Schlagwörter: Prion protein; Neurodegenerative diseases; Neuroprotection
Erscheinungsdatum: 2019
Tag der mündlichen Prüfung: 2020-02-21
The highly conserved and constitutively active endogenous α-cleavage of the prion protein has so far mostly been linked to protective effects. As a soluble factor, the released unstructured N1 fragment acts beneficially in several ways. For instance, it reduces hypoxia-induced neuronal damage and is involved in myelin maintenance. Many studies have shown that N1 is able to block toxic oligomers, such as Aβ which is abundantly produced in Alzheimers disease, and interferes with their synaptic impairment and neurotoxicity.
However, for prion diseases, a potentially protective role of N1 by a similar mechanism neutralizing PrPSc oligomers and interfering with prion conversion has not been studied yet. Since the protease responsible for the α-cleavage has not been identified, pharmacological targeting of this entity is not yet possible. We therefore directly addressed this issue in vivo by generating transgenic mice (TgN1) overexpressing N1 on a wild-type background and challenging them with prions. Despite moderate differences in PrPSc formation and p38 activation, incubation times and disease duration were similar between TgN1 mice and wild-type littermate controls. Biochemical and morphological assessment of brain samples, primary neurons, and cell culture models then revealed that our direct “protective” strategy failed due to cytosolic accumulation and lack of secretion of the transgenic N1. Nevertheless, this work provides the first in vivo proof of the recently described impaired translocation of intrinsically disordered peptides into the endoplasmic reticulum. Moreover, it demonstrates the effects of cytosolic accumulation of N1 with uncleaved signal peptide, addresses proteasomal degradation, questions the general relevance of cytosolic prions in prion diseases, and highlights important aspects to be considered when investigating the α-cleavage of PrPC or devising N1-based therapeutic approaches. To study the potential neuroprotective effect of N1 in the future, a second transgenic mouse model overexpressing N1 fused to a Fc tag was generated and its initial characterization will be provided here.
URL: https://ediss.sub.uni-hamburg.de/handle/ediss/6228
URN: urn:nbn:de:gbv:18-103440
Dokumenttyp: Dissertation
Betreuer*in: Lohr, Christian (Prof. Dr.)
Enthalten in den Sammlungen:Elektronische Dissertationen und Habilitationen

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