CHEM 106

As we learned from the videos last week, proteins are some of the most important components of our bodies. A protein is complex; it has four structures – a primary one that orders the amino acids in a protein, a secondary structure which can be in the form of an alpha helix, a beta sheet or a random coil, a tertiary structure that is a complete 3D structure of the protein including all the atom components and a quaternary structure which consists of multiple proteins/peptides joined together. If there is a problem or mutation in this complex protein structure, it can give rise to severe diseases such as sickle cell anemia.

While we have focused on the prion disease in these past few weeks, research suggests that protein misfolding is also responsible for some of the worst neurodegenerative diseases such as Alzheimers and Parkinsons. While Prion disease, as we learned, occurs in fewer people, Alzheimers accounts for 60% of cases of dementia and has affected over 5 million people in the US alone.

Alzheimers occurs because of an accumulation of a misfolded protein that causes a plaque in the brain. Chromosomes release a small protein to deliver messages. When this protein is released, it folds and if misfolding occurs and accumulates, it prevents brain cells from operating and communicating with one another. Thus it is of the utmost importance to understand proteins and the diseases that result from misfolding so that a cure can be developed, not only for the Prion disease but also for so many other neurogenerative diseases such as Alzheimers and Parkinsons.

Source: https://www.osc.edu/press/researcher_simulates_alzheimers_protein_misfolding_errors

As Susan Lindquist noted the history of Mad Cow Disease in her video, my mind has wandered to the social occurrences which accompany diseases and plagues that have wiped out many peoples throughout history.  As I further questioned the origination and spread of this disease, I discovered that the disease initiated in the Sheep equivalent of the Prion Disease.  This was then passed to Cows as the Cows fed on the Sheep-meal, and ultimately to humans in the UK.  I do of course question whether or not this would have occurred in humans if we were a vegetarian society, or had let those cows die out before consuming meat again.  Of course, this caution would have taken much greater knowledge at the time, but I can’t help but to be curious if we have escaped other diseases by simply not consuming such plants or animals that have been effected.  Additionally, this statement can be spun the opposite way, in such reasoning that perhaps the consumption of some protein would have the capabilities to combat the Prion Disease.

The analogy in the short video assigned for this week comparing amino acids to words and proteins to paragraphs really helped me understand the differences in primary, secondary, tertiary and quaternary structures. As we learned in class, there are many different R groups that differentiate amino acids. This variable is similar to the 27 letters in the alphabet. However, as the video points out, you don’t think of random letters you think of words and then the letters that compose them. Similarly, our DNA codes for certain orders of amino acids that are read and used in different ways.

Primary structure is the order of amino acids in a protein, which is similar to the order of words in a sentence. Like a sentence, you read chains of amino acids or peptides in a certain order—from the N terminus or the capital letter to the C terminus or the period.

Secondary structure is a repetitive three dimensional structure of a protein which is analogous multiple sentences following each other in a chain expressing the same thought or working towards the same goal. The video continues the analogy to quaternary structure or paragraphs built of words and sentences.

What I found interesting and have been thinking about is how the video neglects to draw an analogy between the three different types of protein secondary structures, alpha helices, beta sheets and random coils to something similar with writing. I’m not entirely sure one exists because in English we string words together to follow certain grammatical rules. Perhaps an analogy would be to different grammatical structures that are found in other languages? I’m not totally sure about this and would like some input—I’m interested to see if this kind of analogy can pan out further or if it is limited to what is included in the video we watched.

Hemoglobin is an important substance in the body. It is an iron-rich protein that helps transport oxygen around the body. A disease that results from problems with hemoglobin is sickle cell anemia. Sickle cell anemia is a hereditary disease. It results in often debilitating chronic pain and fatigue. Its name comes from the fact that red blood cells, instead of being oval in shape, are curved like a sickle. There is no cure for sickle cell anemia, though bone marrow transplants can sometimes be used as a treatment to lessen the severity of symptoms.

The mechanism of this disease is much like the mechanism of neurological proteopathies. The sickle cells are rigid and stick to each other because of their structure. This results in blockages in blood flow which can cause pain, organ damage, and infection. This is much like the problems that arise in prion diseases such as Bovine spongiform encephalopathy, fatal familial insomnia, and kuru. Unlike Kuru, sickle cell anemia does not have an incubation period, nor does it result in death as quickly. But, the lifespans of people with sickle cell anemia are significantly shorter than individuals without sickle cell anemia. They live until their forties and fifties.

http://www.nhlbi.nih.gov/health/health-topics/topics/sca

https://www.youtube.com/watch?v=iKQmQHh4E2w

Last week we learned about primary structures of proteins: the order of their amino acids. We know that the secondary and tertiary structure of the prion protein causes it to be normal versus infectious, so I was curious about the primary structure of the prion proteins. I assumed it was always the same, but found out via a little research that this is not the case. Sometimes, different amino acids are in different places in the prion. This does not change the overall structure/function of the protein, but it can have smaller effects.

For instance, for Chronic Wasting Disease in deer and elk, there appear to be two strains of prion diseases caused by a variation in the primary structure of the protein. These strains are differentiated by their incubation times and different neuropathological patterns. Apparently the variations that might have caused these differences relate to the difference in residue 226 of the elk prion protein, which can be glutamic acid or glutamine.

Another instance of primary structure affecting prion disease is found in humans, at codon 129 of the human prion protein gene. It can encode for either methionine or valine. This difference can cause changes in how susceptible a human is to sporadic and/or infectious prion diseases. It can also affect the age of onset for prion diseases. These differences may even affect the mechanism and kinetics of the protein unfolding and refolding into the maladaptive form.

It seems that changing a couple amino acids does not affect the overall stability of this protein, but does affect how it unfolds/folds. Differences in the hydrophobic interactions might then affect how the proteins are attracted to each other/interact with each other, leading to the differences in protein aggregation that cause differences in how the disease starts.

So, we’ve been learning about the prion protein for a while now but this entire time we’ve ended conversations with “but there is not cure” which is pretty sad because people who contract prion diseases are suffering terrible deaths. They die -completely aware- trapped inside their incapacitated bodies. What could be worse?

It’s like being buried alive, right?

But science might have an answer. Professor of Neuropathology at the University of Zurich and University Hospital Zurich, Adriano Aguzzi has been studying  the prion protein and he and his team believe they have figured out the nature, at least, of the prion protein and perhaps the cause of its toxicity. While prion proteins are usually harmless and can be found in our brain’s cell membrane, when a prion protein is touched by a foreign molecule on its tail, the protein goes nuts and becomes toxic. Aguzzi believes the protein has a switch and when triggered, the tail, a separate part from the globular head, causes the prion protein to become deformed and clumped which ultimately leads to cell death. Aguzzi suggests only those antibodies that attack the tail of the prion protein are suitable as potential drugs for combating the disease, which seems like a great start to curing the disease.

So far during the semester, we’ve discussed scientific structures by starting with the smaller parts and working up to the larger compositions. As we learned, protons, neutrons and electrons compose atoms. Each atom is distinguished by a different number of each of its components. This past week, we learned how amino acids, of which there are but 20, are the monomers or individual building blocks of proteins. We looked one step further back than just the amino acid itself. Amino acids are composed of an alpha carbon, an amino group (NH3+), an acidic carboxylate (COO-), a hydrogen atom (H) and the variable group (symbolized by “R”) that differentiates each of the 20 amino acids from one another. It is that variable side chain element that then names the amino acid.

Further, amino acids bond together by carboxyl and amino groups forming a peptide bond in a reaction that also creates water as a byproduct. Peptide bonded amino acids are then called amino acid residues because they have somewhat altered their structure from that of a single amino acid. So, amino acids are then monomers themselves of peptides and polypeptides and ultimately proteins when the chains are long enough.

Proteins appear to be irregularly shaped which helps them serve their wide array of jobs within organisms. They are an integral part in the functioning of a human and animal body. Proteins fold in on themselves encompassing a hydrophobic core with a hydrophilic outer surface. But, before they can form their hydrophobic core, the proteins must first fold. They fold into either α helices or β sheets depending on the requirements of the hydrogen bonds. An α helix is a helical structure enforced by hydrogen bonds between the C=O and the NH group of another amino acid residue 4 spaces ahead of it in the chain. This pattern causes the spiral helical shape. A β sheet on the other hand is formed by two or more β strands of proteins, which are formed by the interaction between two different amino acid residues. β sheets are flat and line up together, often in sets of 4 with two parallel strands in the middle surrounded by two additional strands in other directions on the outside.

The complexity of proteins that we learned about this past week has helped me understand why when a prion causes a different folding, it has such dire consequences.

As we have learned, prion disease is essentially PrPc that transforms into a malicious variant which has a negative effect on the nervous system and likewise, a negative effect on the memory and other cognitive functions.  Per the research and imagery provided by the video from the neuropathologists of the University of Zurich and the University Hospital Zurich, it seems the surfaces where the antibodies and the prion protein are connected is not a very large surface.  If I understand correctly, the thickness of the slice has a correlation with the prion protein’s characteristics; thus with a smaller amino terminal there is no possibility for toxicity.

This is all based on previous research in junction with further hypotheses.  It is fascinating that these such protein reactions can be predicted given both their complexity in general and their complexity in observation.  I would be interested in further understanding the thought process of scientists in the trajectory of their thinking of how to address genetic diseases.  As an anthropologist, I would have focused more on the lifestyle practices that could progress the mutation and formation of the prion disease.