When proteins are made for the purpose of secretion out of the cell or integration into the plasma membrane, they are first folded in the endoplasmic reticulum (ER) (Braakman & Hebert, 2013). This folding process is carefully monitored by a group of signal transducers known as the unfolded protein response (UPR) (Bravo et al., 2013). If misfolding occurs, the UPR works as part of the proteostasis network including molecular chaperones, protein degradation machinery, and stress response pathways, to correct the misfolding (Labbadia & Morimoto, 2014). As a person ages, their unfolded protein response begins to break down which leads to an increase in misfolded proteins (Labbadia & Morimoto, 2014). Many age-onset disorders such as Parkinson’s and Alzheimer’s can result from this accumulation of misfolded proteins (Matai et al., 2019).
An article in Proceedings of the National Academy of Sciences (PNAS) suggests that dietary restriction might lead to an increase in UPR, preventing the misfolding of proteins and leading to a longer life span (Matai et al., 2019). The researchers examined this effect by inducing dietary limitations in round worms, caenorhabditis elegans (Matai et al., 2019). The amount of glucose that is ingested is decreased which leads to a reduced amount of protein glycosylation shown (Matai et al., 2019). This process acts as a mild stressor on the endoplasmic reticulum and up-regulation of the UPR occurs (Matai et al., 2019). Exposing the round worms to dietary restrictions early in their life showed an increase proteostasis network function into adulthood (Matai et al., 2019).
Pharmaceutical drugs that restrict glycosylation such as tunicamycin were also examined in mammalian cells to determine their effect (Matai et al., 2019). They were found to up-regulate UPR in cells as well (Matai et al., 2019). These findings reveal that reducing glycosylation (via diet or medication) in the ER can allow UPR to maintain high activity and potentially lead to delayed onset of disease that result from misfolded proteins (Matai et al., 2019).
Braakman, I., & Hebert, D. N. (2013). Protein folding in the endoplasmic reticulum. Cold Spring Harbor Perspectives in Biology, 5(5), a013201. https://doi.org/10.1101/cshperspect.a013201
Bravo, R., Parra, V., Gatica, D., Rodriguez, A. E., Torrealba, N., Paredes, F., Lavandero, S. (2013). Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration. International Review of Cell and Molecular Biology, 301, 215–290. https://doi.org/10.1016/B978-0-12-407704-1.00005-1
Labbadia, J., & Morimoto, R. I. (2014). Proteostasis and longevity: When does aging really begin? F1000Prime Reports, 6. https://doi.org/10.12703/P6-07
Matai, L., Sarkar, G. C., Chamoli, M., Malik, Y., Kumar, S. S., Rautela, U., Mukhopadhyay, A. (2019). Dietary restriction improves proteostasis and increases life span through endoplasmic reticulum hormesis. Proceedings of the National Academy of Sciences, 116(35), 17383–17392. https://doi.org/10.1073/pnas.1900055116
This is a very interesting paper. It’s interesting that a decreased in glycosylation could lead to lead to longer life span. As we know from physiology glycosylation is a huge part of post-translational modification. Do you think that lowered glycosylation could have negative effects on post-translational processes? Also, I am interested in understand what is an appropriate amount of glucose intake per day? There have been studies that link hypoglycemia to an increase in cardiovascular risks (Frier et al., 2011).
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Frier BM, Schernthaner G, Heller SR. Hypoglycemia and cardiovascular risks, Diabetes Care , 2011, vol. 34 Suppl 2(pg. S132-7)
This is a very interesting idea because it adds more emphasis on the importance of diet/nutrition on health and well-being. I know that you mentioned the previous study restricted glucose in round worms, but I was wondering how drastic this restriction was or if it would even be possible to mimic this kind of diet in human . subjects? Very regimented and restrictive diets are usually not good long term solutions as people are often unable to follow them for an extended period of time (Wei, M., et. al., 2017). I like how you also included the pharmaceutical possibilities because it addresses alternative means to achieve this effect without having to overcome the barrier of patients following a diet and I feel as though it is very applicable in this day and age. Furthermore, I appreciate Erin's comment as well because when I was doing some research on this topic, there appears to be multiple possible implications for dietary restrictions and health outcomes!
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Wei, M., Brandhorst, S., Shelehchi, M., Mirzaei, H., Cheng, C. W., Budniak, J., Groshen, S., Mack, W. J., Guen, E., Di Biase, S., Cohen, P., Morgan, T. E., Dorff, T., Hong, K., Michalson, A., Laviano, A., & Longo, V. D. (2017). Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Science Translational Medicine, 15;9(377). doi: 10.1126/scitranslmed.aai8700
This is a very interesting topic, especially since we are finding more and more about the dangers of a high-sugar and high processed food diet. Like Savanna said, it would be interesting to see some sort of similar restrictive diet study done in humans. When it comes to protein mis-folding, the first thing that comes to mind is Alzheimer's disease since its prevalence has increased over the years. Links have been found between high levels of glucose and the severity of Alzheimer's (NIH, 2017), so it makes me wonder if this protein glycosylation could be or is a potential target in the treatment of Alzheimer's? It would be interesting to see how a drug like Tunicamycin might mediate protein misfolding in Alzheimer's patients if glycosylation was indeed a factor.
ReplyDeleteThe idea of high glucose negatively impacting the symptoms of Alzheimer's, while low glucose levels have a negative impact on cardiovascular health, as Erin mentioned above, is an interesting example of how complex the body's physiology is when it comes to finding different medical treatments.
Reference:
National Institutes of Health. (2017). Higher brain glucose levels may mean more severe Alzheimer's. Retrieved from https://www.nih.gov/news-events/news-releases/higher-brain-glucose-levels-may-mean-more-severe-alzheimers