The interaction between the circadian clock, temperature entrainment and the insoluble protein content

Rubbe, Nora (2021): The interaction between the circadian clock, temperature entrainment and the insoluble protein content. Dissertation, LMU München: Medizinische Fakultät

Abstract

The elderly and patients suffering from age-associated neurodegenerative diseases (ND) often present with disrupted circadian timing systems such as alterations in their wake-sleep cycle. As aging and ND are associated with an increase of protein aggregates in the brain tissue, a correlation between protein aggregation and a disrupted circadian timing system seems likely. This study aims to investigate the effect of the circadian clock on protein aggregation in aging neuronal cells. We established an aging neuronal cell model by inducing senescence with administration of a histone deacetylase inhibitor (LBH589) in mouse neuroblastoma cells (N2A cells). One hallmark of senescent cells in an increase of protein aggregates. Therefore, senescent neurons represent a low complexity in vitro model for aging cells in which to test discrete hypotheses. In order to investigate the effect of circadian entrainment on protein aggregation in senescent cells, we kept senescent N2A cells in 24 temperature cycles with 34 °C (12 hours) and 37 °C (12 hours). A comparison with control cells kept in 24h temperature cycles or constant temperature showed effects of a 24h zeitgeber cycle on aggregation. Analyses of the protein content in N2A cells kept in temperature cycles revealed a decrease in insoluble protein content compared to cells kept in constant temperature condition. However, we observed no differences in the insoluble protein content of cells kept in 24h versus non-24h temperature cycles. Therefore, we suggest a direct effect of temperature on the insoluble protein content in N2A cells, without a significant influence of circadian clock oscillation. These findings support the hypothesis that the master pacemaker of the circadian timing system, the suprachiasmatic nucleus (SCN), influences protein aggregation through regulating temperature amplitudes and not as initially expected through circadiantemperature amplitudes. An impaired SCN and temperature alterations in elderly and ND patients, suggested by several studies, may influence the proteostasis network adverse. Therefore, a better rhythmicity (like activity at day time, sleep during night) in elderly could lead to a better entrainment of the SCN and higher temperature amplitudes, which would protect the cell from protein aggregates and thus could be a therapy option for ND in future. Furthermore, the effect of protein aggregates on cell survival could be a focus of future projects. If decreasing the insoluble protein content of a cell is beneficial, this could represent a target for new therapeutic approaches to treat or even prevent neurodegenerative diseases.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 30. September 2021
• 1. Bericht­erstatter:in: Merrow, Martha