Schlafregulation im genetischen Mausmodell für tödliche familiäre Schlaflosigkeit
Zusammenfassung der Projektergebnisse
In this project, we characterized the sleep and EEG phenotype of the knock-in FFI mouse model (a mutation of the Prnp gene). The impact of the mutation on the ability to sleep was surprisingly small. Therefore, we replaced the originally planned functional histology part with two further studies that aimed to characterize the influence of Prnp on sleep in more detail. By comparing mouse models for FFI, CJD, and scrapie (RML) with Prnp knockout and appropriate negative controls, we were able to identify an EEG-based biomarker for prion protein misfolding pathologies. This biomarker is the relative EEG theta power (5-10 Hz), which is elevated in all three models irrespective of the observed vigilance state (wake, NREM, or REM sleep), but not in KO mice. By employing longitudinal analysis of repeated 24 h recordings throughout disease progression in the RML model of scrapie, we were able to demonstrate that this biomarker is disease-tracking. A recent independent study reported that EEG theta is elevated in human prion protein misfolding diseases as well. Thus, this biomarker is transdiagnostic (applies to different prion diseases) and translational (applies to patients as well as preclinical mouse models). We propose that relative EEG theta power will be highly useful to track disease progression in longitudinal study designs and greatly facilitate the study of disease modifying interventions. We have already applied this marker to identify the most interesting time points for a gene expression study of the RML scrapie mouse model in a separate study in the lab. During this project, a new study reported that the Disc1 gene is involved in sleep regulation. Since our background strain, 129S4, carries a natural deletion mutation of Disc1, we wondered if this might have masked the effects of the FFI mutation on sleep. We realized that such an effect could have confounded a wide range of published studies in the field, because this mutation is present in several widely used mouse strains, especially ones commonly used for generating genetically modified mice. Therefore, we dedicated an additional study to the question if the endogenous mutation of the Disc1 gene affects sleep. We employed a back crossing approach to obtain a mouse with our standard background (129S4) carrying a wild type Disc1 allele from a different background (C57BL/6N). We demonstrated that none of the differences in sleep behavior between 129S4 and C57BL/6N background strains are driven by the Disc1 deletion mutation. Thus, this natural mutation has not confounded our FFI study or other studies in the field. To increase public outreach, I have reported on my research in two science slams (Dortmund and Köln), one 90 min public presentation in a pub (Herbrand’s Köln), and one international TV show (“Bill Nye saves the world”, S2:E2, Netflix).
Projektbezogene Publikationen (Auswahl)
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(2017) “The natural Disc1-deletion present in several inbred mouse strains does not affect sleep”. Scientific Reports 7:5665
Dittrich L, Petese A, Jackson WS
