1. Based on your research into Alzheimer’s disease and your interview, how are these two disorders alike?
Both FFI and Alzheimer’s disease are characterized by degeneration of the brain and accumulation of amyloid plaques. However, FFI amyloid plaques are the result of prion protein fragments and amyloid plaques in Alzheimer’s disease are the result of amyloid precursor protein (APP) fragments. The onset of both diseases does not occur until after child-bearing years. Both diseases cause severe dementia in the end stages and are fatal. The forebrain is the main component affected in both diseases, with the thalamus being most affected by FFI, and the cerebral cortex and hypothalamus being most affected by Alzheimer’s disease. Individuals with either disease exhibit hallucinations, disruption of circadian rhythms (night-day/ sleep-wake cycles), and loss of the ability to speak. The families of individuals suffering from these diseases are forced to provide an increasing amount of care to the individuals as the disease progresses. Another difference is that it is unknown if Alzheimer’s is hereditary where as FFI is hereditary.
2. What are prions?
Prions are proteins (PrPC ) which naturally occur in the human body and are associated mainly with brain tissue. A mutation in the PRNP gene which codes for the prion protein causes an abnormal form of the prion protein to be produced (PRPSC).The abnormal protein somehow is able to convert normal prion proteins into the abnormal form, and these abnormal proteins clump together forming amyloid plaques that damage or destroy nerve cells. (http://ghr.nlm.nih.gov/condition=priondisease)
3. FFI is an autosomal dominant disease, meaning that if an individual inherits just one dominant allele from either parent, they will develop the disease. However, this disease does not manifest itself phenotypically until after reproductive age. So can this disorder be acted on by natural selection? What about Alzheimer’s? What is maintaining these disorders in the population?
No, this disease cannot be acted on by natural selection because natural selection works on the phenotype of an individual, which appears normal in individuals with FFI until after child bearing years. An individual may have already produced offspring with the mutation before their own maladaptive traits even surfaced. However, genetic testing allows a couple to know if one or both of them possess the genetic abnormality and therefore may pass the gene to offspring. The same is true for Alzheimer’s disease, although Alzheimer’s is thought to be less heritable than FFI. These disorders are maintained in the population due to mutations, as well as the lack of phenotypic manifestation prior to reproductive age.
4. FFI is caused by a single mutation that, in the presence of methionine at amino acid position 129, changes aspartic acid to asparagine. This same mutation, in the presence of valine at position 129, causes a separate prion-disease called Creutzfeldt-Jacob syndrome. In cattle, the homologous syndrome is Mad Cow disease. How can studying protein folding and mis-folding help in understanding diseases like these?
Proteins are formed from long, linear chains of amino acids and fold into shapes that depend on the properties of the amino acids of the chain. Properties such as hydrophobia, hydrophilia, electrical charge, etc, (http://en.wikipedia.org/wiki/Protein_folding#Incorrect_protein_folding_and_neurodegenerative_disease). In the missense mutations that cause prion diseases mentioned above, different amino acids are inserted into the chain of amino acids. When the protein folds, the different amino acid has dissimilar properties to the amino acid that was meant to be in that spot and therefore folds the protein differently. This new folding may cause the protein to have a new function or, most likely, it will cause the protein to be non-functioning.
So studying the properties of amino acids can help to predict how proteins will fold. Also, studying how proteins with known amino acids sequences fold can help predict what properties different amino acids have. If researchers could discover the shapes of all proteins, then early detection of misfolding could be a possibility in the future of science and medicine.
**This disease was discussed last week on Medical Mysteries: (http://video.google.com/videoplay?docid=760959254431325673&q=fatal+familial+insomnia&total=3&start=0&num=10&so=0&type=search&plindex=0)
The two sisters in this story lost their mother to FFI. One sister chose to be tested for the mutation, while the other sister did not. Would each of you want to know whether or not you had a disease such as this, or would you rather remain unaware?
Katie – I would want to know if I had the disease. If I knew that I would possibly develop the disease then I could get all of my affairs in order while I was still lucid enough to make rational and well thought out decisions. I would also be able to prepare my family for what would happen with the disease began to appear and progress. If I chose not to be tested then I would always be wondering if I had the disease or if and when I would develop the symptoms. But if I was tested and the results showed that I was free of the disease, then I would be freed from constant worry and would be able to more fully enjoy the rest of my life.
Hailey – I would definitely want to be tested for the mutation that causes FFI. Although I would feel a great deal of anxiety if I found that I had it, I think I would feel an even greater sense of anxiety if I did not know. Discovering the presence of this mutation in me and knowing what my future held would be beneficial knowledge. Like Katie said, I could get everything prepared for my family so there would less stress with my death. Also, I could make arrangements for myself for when I reach the stages of the disease that require much care. Overall, getting tested would leave me with more peace of mind than not being tested.
Megan- I don't think that I would want to know if I had the mutation. I think that it would cause me and everyone else around me to live life differently. I am a reasonably care free person, and the last thing that I would want to do is make others worry and walk on egg shells around me. There are any number of things that could happen to me at any time, so even if I knew about the mutation, I still couldn't plan for the future, becuase I don't know what else may happen. If I had the mutation, I would deal with it when I had no other choice. It would already be taking away enough of my time, and I wouldn't want to spend my time before planning for it.
