Understanding Circadian Rhythms and the Connection to Parkinson's Disease

 Many organisms, such as mammals, plants, fungi, and cyanobacteria, have circadian rhythms, which are approximately 24-hour cycles that regulate many essential biological processes. These processes include feeding, body temperature, sleep cycles, and hormone release, which are driven by the internal clock system, which appear in various tissues. This allows animals to relate behavioral and physiological processes to each other, and for these processes to synchronize in response to external environmental cycles (Cavanaugh et al. 2019). For example, an organism can adapt its circadian rhythm to the rising and setting of the sun to optimize maximum feeding and sleeping times (Allada and Chung 2010). 

    Drosophila melanogaster, more commonly known as the fruit fly, has demonstrated its effectiveness as a model for studying circadian rhythms due to their low cost, rapid generation time, analogous human genealogy and anatomy, and easily manipulable genetic tools (Towlinski 2017). The easy-to-manipulate genome of Drosophila melanogaster in research lead to the discovery of the period (also called per) gene, which was imperative to understanding circadian rhythms at a molecular scale. The per gene was the first clock gene to be discovered, and modulates the circadian rhythm in Drosophila. Upon further research, the timeless (tim) gene was discovered, and works alongside per to create a transcriptional feedback loop, driving the expression of two transcriptional activators, called clock (CLK) and cycle (cyc). Together, all four of these genes in neurons make up the internal clock, which controls circadian rhythms. This negative feedback loop controls circadian rhythms by utilizing per and tim, which shut off their own transcription during the night by binding to clk and cyc. Next, the per and tim genes move from the cytoplasm of clock-containing cells to the nucleus. The interval of tim and per proteins in the cytoplasm partially determine the period length which equates to approximately 24 hours (Meyer et al. 2007). 

In the paper, “Central and Peripheral Clock Control of Circadian Feeding Rhythms,” Cavanugh et. al dive deeper into the world of circadian rhythms, and discuss “the cells and circuits mediating circadian control of feeding behavior” (Cavanaugh et al., 2021). The aim of their research is to further explore Drosophila rhythms, not just those that generate locomotor activity, but how the circadian rhythm plays an orchestral role in mediating and regulating behavior. The relationship of the core clock genes is instrumental in driving the function of circadian rhythms in Drosophila. PER and TIM genes are driven by CLK and CYC, and their activation creates the transcriptional-translational feedback loop that creates a circadian rhythm. PER and TIM degradation takes approximately 24 hours. While it is understood that the central clock shows the mechanisms of feeding:fasting rhythms, this group of researchers work to question and understand the role of a likely contributor, the peripheral clock, and its unique characterization. To do this, these researchers utilized FLIC analysis under LD (light, matching fly entrainment schedules) and DD (total darkness) conditions to monitor the amount of times that flies interacted with food via a voltage signal. The results of the FLIC analysis demonstrated  the lack of effect of fat body clock speed manipulations on the timing of feeding and Pdf>sgg hypo flies display short period feeding rhythms in contrast to Pdf>dbt L flies, which had longer period feeding rhythms. By these results, it was reaffirmed that flies with a mutant CYC gene did not have as strong of a DD feeding rhythm as the control flies, which solidified the knowledge that this is a circadian-controlled process. Additionally, Cavanaugh et al. concluded that the role of peripheral clocks in feeding does not impact the behavior. These peripheral clocks play a role in generating these feeding rhythms, but are not necessary for normal feeding rhythms by genetic elimination. However, both of these clocks contribute to feeding rhythm regulation. This research is compelling, but leaves room for more questions, specifically how does this research be applied to larger, more complex organisms, like humans?

The University of California at San Francisco provides a promising answer to how circadian rhythm research can be applied to humans. Parksinson’s is a disease that degenerates DOPAminergic neurons in the substantia nigra, and is “a disease characterized by loss of control over movement, balance and other brain functions”(ScienceDaily 2020). The UCSF researchers found that in their “longitudinal study of 2930 community-dwelling older men without Parkinson's disease at baseline, the risk of incident Parkinson's disease increased significantly with decreasing circadian amplitude, mesor, or robustness. Participants in the lowest quartile for these measures had approximately 3 times the risk of developing Parkinson's disease compared with those in the highest quartile” (Leng et al 2020). This conclusion indicates that circadian rhythm disruption is an indication of early-onset Parkinson’s disease, successfully and effectively showing the importance of circadian rhythms on a complex organism scale.

Literature Referenced

Allada, R., & Chung, B. Y. (2010, March). Circadian organization of behavior and physiology in drosophila. Annual review of physiology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2887282/ 

Dreyer, A. P., Martin, M. M., Fulgham, C. V., Jabr, D. A., Bai, L., Beshel, J., & Cavanaugh, D. J. (2019, November 6). A circadian output center controlling feeding:fasting rhythms in drosophila. PLoS genetics. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6860455/ 

Fulgham, C. V., Dreyer, A. P., Nasseri, A., Miller, A. N., Love, J., Martin, M. M., Jabr, D. A., Saurabh, S., & Cavanaugh, D. J. (2021). Central and Peripheral Clock Control of Circadian Feeding Rhythms. Journal of biological rhythms, 36(6), 548–566. https://doi.org/10.1177/07487304211045835

MW;, S. L. M. P. Y. (2007). A per/Tim/DBT interval timer for drosophila's circadian clock. Cold Spring Harbor symposia on quantitative biology. https://pubmed.ncbi.nlm.nih.gov/18419263/ 

NS;, T. (2017, September). Introduction: Drosophila-A model system for developmental biology. Journal of developmental biology. https://pubmed.ncbi.nlm.nih.gov/29615566/ 

ScienceDaily. (2020). Disrupted Circadian Rhythms Linked to Later Parkinson's Diagnoses. ScienceDaily, https://www.sciencedaily.com/releases/2020/06/200615142802.htm. 

Yue Leng, MD. (2020). Association of Circadian Abnormalities in Older Adults with an Increased Risk of Parkinson's Disease. JAMA Neurology, JAMA Network. https://jamanetwork.com/journals/jamaneurology/fullarticle/2767087.