Role(s) of protein misfolding in ALS
Recently, a brief review on amyotrophic lateral sclerosis (ALS) was written. This 6-page pdf file can be found at the following hyperlink:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3395178/pdf/NRI2012-323261.pdf
ALS, more commonly called Lou Gehrig's disease, named after the famed baseball great who suffered from this malady, can be characterized either as familial ALS (genetic) or as sporadic ALS (sALS). It is caused by a gain of toxicity mutation in a Cu, Zn-superoxide dismutase (SOD1) gene. For the familial disease, it is a dominant mutation.
Superoxide dismutases, in general, are enzymes that catalyze superoxide, a harmful radical, into oxygen and hydrogen peroxide. These enzymes are essential in keeping proper antioxidant homeostatic control in vivo.
First, read the brief review concerning the advances being made in ALS research, paying particular close attention to the structure-function--or perhaps it is better to say structure-disfunction--relationships.
Then, post a blog response outlining a brief synopsis of this article. Within this response, I also want you to hypothesize/speculate, given what we have been discussing thus far in Biochemistry, how these mutations result in the given phenotype.
For more information, please see the website for the ALS Association.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3395178/pdf/NRI2012-323261.pdf
Superoxide dismutases, in general, are enzymes that catalyze superoxide, a harmful radical, into oxygen and hydrogen peroxide. These enzymes are essential in keeping proper antioxidant homeostatic control in vivo.
First, read the brief review concerning the advances being made in ALS research, paying particular close attention to the structure-function--or perhaps it is better to say structure-disfunction--relationships.
Then, post a blog response outlining a brief synopsis of this article. Within this response, I also want you to hypothesize/speculate, given what we have been discussing thus far in Biochemistry, how these mutations result in the given phenotype.
For more information, please see the website for the ALS Association.
Interestingly enough the first thing that came to mind when I read about the aggregation of insoluble proteins caused by the mutation was the need for chaperonins. According to my limited knowledge on the issue (do in part to my 3 whole weeks of Biochemistry) I believe the biggest problem is due to the lack of an efficient chaperoning mechanism. Though the SOD1 gene is mutated, resulting in the production of misfolded proteins, chaperones should be able to assist in the correction of such anomalies.
ReplyDeleteCharacteristic of all proteins, intramolecular interactions of the wild-type SOD1 play a key role in minimizing the propensity for misfolding to occur. The mutated SOD1 protein most likely differs in its primary sequence thus changing the intramolecular interactions. According to the article, the stability of SOD1 wild-type increases dramatically due to the formation of disulfide bonds, a characteristic the mutated protein lacks. I would assume the mutant protein’s decreased stability stems from a positional change, or complete deletion of a cysteine (Cys) residue. If the Cys residue is not in the appropriate spot in order for the normal conformation to form, via RSSR bonding, the protein will most likely fold into a different, energetically unfavorable conformation. The lack of stability could possibly increase the propensity for the protein to aggregate. I wonder if there would be any way for chaperones to guide the misfolded proteins back into their normal, more energetically favorable shapes. If that would be possible the likelihood of aggregation would probably decrease.
I also found it interesting that aggregation could form among wild-type SOD1. When SOD1, lacking, zinc were mixed with CuCl2 aggregates formed. This was a result of histidine (His) residues affinity for Cu, as discussed in class. Just as disulfide bonding affects the structure and function of this protein so does the metal ion interaction between His and Cu. The ability for both mutated and wild-type SOD1 to produce aggregates made it clear to me that the issue is so much more greater then a misfolded protein but also include the co-factors, or lack there of, in the wild-type.
Great job, Jessica! I like how you have incorporated themes from class in your response.
DeleteFirst off this article was a great read due to the fact that I have never heard of this disease. It was great to be informed on a disease that focuses on the role of protein folding, after learning about how that has significant influence on a person’s body. Overall the article discussed a disease called amyotrophic lateral sclerosis (ALS). This disease is connected to protein misfolding and aggregation. The first part of this article that stood out to me was the fact that they do not have a cure to this disease; however they do know the gene that is involved with causing this disease. I believe that if you have at least a piece of what is causing this disease than you should be able to at least work backwards to find a cure. (Easier said by an undergraduate student than done) I think that since they know that this gene encodes a protein that then increases insoluble aggregation, they should know that they need something to control that protein (Cu, Zn-superoxide dismutase). In class we learned about protein folding, and when there is misfolding we know that this results in disease. In order to control this misfolding there are chaperones that aid in controlling protein folding. If there was some way that researchers could test the SOD1 protein with a chaperone that controls that protein folding then maybe that would help. This is just an opinion but there is evidence that if protein folding is controlled then disease cannot occur. Although there was a chaperone mention (CCS) it didn’t seem to be affective because the misfolding was still occurring. This chaperone is a copper ion which isn’t affecting the folding, maybe there is another metallic interaction that could change the folding of the protein. This article also mention that healthy people “SOD1 correctly processed to acquire metal ion and disulfide bonds which prevents aggregation”, which means that there has to be proper interactions to prevent disease. We learned that protein structural stability is important; you must have hydrophobic interactions, hydrogen bonding, formation of disulfide bonds, and ionic interactions. Although there were parts of the article that were a little difficult to understand I was still able to gain more knowledge on how important protein folding is.
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ReplyDeleteIn order to better understand Lou Gehrig’s disease (ALS), one must really understand the relationship between structure and function. As structure dictates the function in all biological processes, an error at the molecular level can prove to be deadly to the organism, which is the case for ALS. From what scientists already know, a mutation in the SOD1 gene has been one of the supposed “causes” for the diagnosis of ALS. Normally, the SOD1 gene encodes for an enzyme called Cu, Zn-superoxide dismutase which converts a superoxide anion into oxygen and hydrogen peroxide but when a mutation occurs in the gene’s genetic sequence (due to a deletion or an insertion of a nucleic acid) this jeopardizes the proper translation of Cu, Zn-superoxide dismutase. This mutation interferes with the protein’s ability to make disulfide bonds and disables the proper attachment of metal ions to itself. This lowers the overall stability of the protein’s tertiary structure and it becomes unused by the cell because it cannot perform its proper function to detox the superoxide anion due to the inability of the superoxide anion to bind to the enzyme. An accumulation of the misfolded proteins also results in the accumulation of the superoxide anion which eventually kills the cell because of the increased toxicity of the anion within the cell. Unlike other cells in the body, neural cells do not keep multiplying throughout a person’s life so when the cells die, it slows down the nervous impulses and leads to the common symptoms exhibited in ALS.
ReplyDeleteOne thing that the other author did not mention that I would have liked to know about is the presence (or lack of presence) of a degradation enzyme or the role of the lysosome in this disease. As I read this article, I was wondering why the cell does not signal for the misfolded proteins to get eaten by the lysosome or degraded by another protein like it usually does when it disposes of ineffective proteins and molecules.
Great job, ladies!
ReplyDeleteThis was a great article to read especially after just lastnight having a conversation about how many athletes who sustain massive head injuries end up with ALS. It was interesting to read that one tenth of the cases if ALS are familial and the rest are sporadic. The article in the link below highlighted an interesting finding by Dr. Ann Mckee, a neurology professor at Boston University. She found that after studying three athletes that were diagnosed with ALS. McKee found toxic proteins in the spinal cords of the three athletes that had sustained head injuries and were later diagnosed with Lou Gehrig's disease. She noticed that the same proteins were present in the brains of athletes with chronic traumatic encephalopathy (CTE). However the proteins were not present in the spines of athletes with CTE nor in the spines of patients who had died with ALS.
ReplyDeletehttp://www.nfl.com/news/story/09000d5d819d12df/article/scientists-link-athletes-head-injuries-alslike-disease
Reading these two articles really sparked in me an interest as to whether all the sporadic cases of ALS are in fact ALS or this newly discovered disorder named by McKee as CTEM, chronic traumatic encephalomyopathy.
The degeneration of motor neurons has a significant effect in patients life, not being able to control voluntary muscle makes easy common tasks in daily life more difficult. The fact that they were able to associate SOD-1 with ALS is an important discovery towards proper treatment. The mutation of SOD-1 is linked to familial ALS, which is being used in the generation of a new drug that is currently on clinical trial. ISIS-SOD1Rx works as an antisense therapy, which tries to impede the production of mutated SOD-1 by binding to mRNA and inactivating it. The success of this drug could improve the life of many ALS patients.
ReplyDeleteMotor neuron degeneration can cause some very serious effects in patients lives. The degeneration can cause involuntary muscle reactions that make every day life extremely complicated. I have always been a long time baseball fan and it has made me very aware about ALS. The fact that a mutation has been discovered in the SOD-1 gene is important to getting proper treatment. A successful drug treatment could be very beneficial to a huge amount of people and could be huge to the scientific community.
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