FINAL PAPER

A Look Into ParkinsonŐs Disease

For my Senior Project I chose to focus on ParkinsonŐs disease. My project is a literary review concerning a self-made hypothesis on the cause of ParkinsonŐs disease, which is a neurodegenerative disease that causes a loss of motor functions. My hypothesis is that the depletion of heat shock proteins by α-Synuclein detoxification raises the amount of oxidative stress on neurons and inactivity of DJ-1 proteins by a mutation in the gene DJ-1, causes neurodegeneration of dopaminic neurons at a high rate. By using a variety of sources I was able to gain evidence to support my hypothesis.

I came to the idea of studying ParkinsonŐs disease at the beginning of the school year. I had various meetings in the summer with Patricia Lein. During one of these meetings she suggested to me to look into Drosophila melanogaster genetics. Drosophila melanogaster is the common fruit fly and is used by laboratories world wide as a model system. After some research into Drosophila, I learned that it has a complex nervous system is able to express a large number of diseases that are present in humans. Neurodegenerative diseases were some of the diseases that laboratories studied with Drosophila.

When I returned to school during the fall I had decided with my mentor, Annemarie Costello to focus on Drosophila studies on ParkinsonŐs disease. After some intensive research into the genetics of ParkinsonŐs disease I shifted my focus towards ParkinsonŐs related genes. Some of these genes included SNCN and DJ-1. After a few weeks I had to decide on a product that would accumulate my research and work into a single object that could be presented. I came to the conclusion of creating a scientific poster that would show and discuss phylogenetic trees of the genes SNCN and DJ-1 over a wide range of animals, as both DJ-1 and SNCN are present in many organisms all the way back to many prokaryotes. In this product I planned to further my understanding of the genetic causes of ParkinsonŐs and phylogenetic analysis. In order to do this I needed the program PAUP, Phylogenetic Analysis Using Parsimony.  Unfortunately PAUP took longer than I had expected to arrive and I was stuck waiting with the date for approval to present approaching quickly. When I had finally received PAUP I discovered that it was not how I expected it to be. Since I was using a new Mac computer, I had to use the command based version of the PAUP. This made it incredibly difficult to create phylogenetic trees, as every command needed a specific phrase and code to be put in. After a few weeks I was still unable to create any trees and lost hope in the project.

With the approval deadline only two weeks away, I had to revise my whole project. Since I had already done a fair amount of research on the genetic causes of ParkinsonŐs, I wanted to stay within that range. My mentor and I decided that I should write a literary review. My new goals in this project was to learn more about molecular genetics. I also wanted to create a reasonable paper that I could present in the scientific community. In order to do this I had to create a hypothesis. After some research into traits that occurred in the ParkinsonŐs effected mind, I created a speculation on what could possibly be behind ParkinsonŐs disease. After I had a basic idea of my hypothesis, I had to do a dramatic amount of research so that my hypothesis would be supported. This continued all the way through my project.

My project hit another snag in January as after a few pages of writing, my computerŐs hard drive died and I lost everything. After a week of the incident I was way past the senior project deadline with no work at all. That weekend I needed to make up for lost time and wrote 18 pages. This was a large step for my project, but unfortunately I had forgotten to make citations in my paper. I could not have a proper paper without citations. Going back doing citations took much longer than I had expected and was a trivial process. When I had finally finished my citations and some more writing, I was ready for my mentor to read my paper. At that point my paper was still in a very rough form, as my hypothesis was still not clearly expressed, I had no opening paragraph, my paper needed more citations and sources, was too dense and had too much jargon, and was loosely put together. With each revision my paper became tighter and more readable. My next issue with my project was that my revisions were taking too long. I had been putting them aside as I had other work. Fortunately as my final deadline approached, I was able to pick up the pace and finish.

I feel that I have accomplished a great deal in this project. I learned a large amount of molecular genetics and about working on a large project. As each paper needed a large amount of knowledge just to read, I was able to greatly enhance my research skills. I also learned that a project of this caliber could never be possibly done over a short period of time. In the future I plan to use this newfound knowledge in college next year to plan out my projects and prevent this from happening again. I still do not know if I will plan to pursue molecular genetics as a career. This project showed me the tedium of such a career. I plan to experiment with other sciences or maybe even take a whole different approach.

Works Cited

Adams, M. D., & al, e. (2000, March 24). The Genome Sequence of Drosophila melanogaster. Science .

Auluck, P. K., Chan, H. Y., Trojanowski, J. Q., Lee, V. M.-Y., & Bonini, N. M. (2002). Chaperone Suppression of α-Synuclein Toxicity in a Drosophila Model for Parkinson's Disease. Science , 295 (5556), 865-868.

Bettencourt, B. R., Kim, I., Hoffmann, A. A., & Feder, M. E. (2002). Response to Natural and Laboratory Selection at the Drosophila HSP70 Genes. Evolution , 56 (9), 1796-1801.

Bonifati, V., Rizzu, P., van Baren, M. J., Schaap, O., Breedveld, G. J., Kriger, E., et. al. (2003). Mutations in the DJ-1 Gene Associated with Autosomal Recessive Early-Onset Parkinsonism. Science , 299 (5604), 256-259.

Bonini, N. M. (2002). Chaperoning Brain Degeneration. Proceedings of the National Academy of Sciences of the United States of America , (99), 16407-16411.

Brain Explorer. (2005, March 2005). Retrieved January 29, 2009, from http://www.brainexplorer.org/

Brown, R. C., Martin, R. L., Hansen, W. J., Beckmann, R. P., & Welch, W. J. (1993). The Constitutive and Stress Inducible Foms of hsp 70 Exhibit Functional Similarities and Interact with One Another in an ATP-dependent Fashion. The Journal of Cell Biology , 120 (6), 1101-1112.

Campbell, N. A., & Reece, J. B. (2005). Biology. New York: Benjamin Cummings.

Clarke CE. ParkinsonŐs Disease in Practice London: Royal Society of Medicine Press Ltd, 2001.

Clements, C. M., McNally, R. S., Conti, B. J., Mak, T. W., & Ting, J. P.-Y. (2006). DJ-1, a Cancer- and Parkinson's Disease-Associated Protein, Stabilizes the Antoioxidant Transcriptional Master Regulator Nrf2. Proceedings of the National Academy of Sciences of the United States of America , 103 (41), 15091-15096.

Cookson, M. R. (2003). Crystallizing Ideas about Parkinson's Disease. Proceedings of the National Academy of Sciences of the United States of America , 100 (16), 9111-9113.

Cotzias G (1968). "L-Dopa for Parkinsonism". The New England Journal of Medicine 278 (11): 630.

Elefant, F. & Palter, K. (1999) Molecular Biology of the Cell (10), 2101-2117.

Fahn S. Parkinsonism. In: Merritt's Textbook of Neurology Rowland LP (ed). (9th edn). Baltimore: William & Wilkins; 1995. pp713–730.

Gandhi, S., Abou-Sleiman, P. M., Healy, D. G., Weale, M., Gliks, W., Ahmadi, K., et. al. (2005). Population Genetic Approaches to Neurological Disease: Parkinson's Disease as an Example. Philosophical Transactions: Biologica Sciences , 360 (1460), 1573-1578.

Gasser T. Genetics of Parkinson's disease Annals Neurology 1998,44:S53–S57.

Goldberg, M. S., Pisani, A., Haburcak, M., Vortherms, T. A., Kitada, T., Costa, C., Tong, Y., Martella, G., Tscherter, A., Martins, A., et. al. (2005) Neuron 45, 489-496.

Jang, H. H., Lee, K. O., Chi, Y. H., Jung, B. G., Park, S. K., Park, J. H., Lee, J. R., Lee, S. S., Moon, J. C., Yun, J. W., et. al. (2004) Cell 117, 625-635. 

Jenner, P. 2000 Pathophysiology and biochemistry of dyskinesia: clues for the development of non-dopamin- ergic treatments. Journal of Neurology. 2(Suppl. 2), II43-II50.

Kinumi, T., Kimata, J., Taira, T., Ariga, H. & Niki, E. (2004) Biochemical and Biophysical Research Communications 317, 722-728.

Krebs, R. A., and B. R. Bettencourt. 1999. Heat shock protein variation and the evolution of thermotolerance in Drosophila. American Zoologist 39:910-919.

Manyam BV, S‡nchez-Ramos JR (1999). "Traditional and complementary therapies in Parkinson's disease". Advances in neurology 80: 565–74.

Mitsumo, A., et. al., Free Radic Research. 35, 301 (2001)

Morgan, T.H. (1910, July 22) Sex Limited Inheritance in Drosophila. Science.

Muchowski, P. J., Schaffar, G., Sittler, A., Wanker, E. E., Hayer-Hartl, M. K. & Hartl, F. U. (2000) Proceedings of the National Academy of Sciences USA 97, 7841-7846.

Paez, G. J., & Sellers, W. R. (2004). PI3K/PTEN/AKT Pathway.

Rossi, M. R., Somji, S., Garrett, S. H., Sens, M. A., Nath, J., & Sens, D. A. (2002). Expression of hsp 27, hsp 60, hsc70, and hsp 70 Stress Response Genes in Cultured Human Urothelial Cells (UROtsa) Exposed to Lethal and Sublethal Concentrations of Sodium Arsenite. Environmental Health Perspectives , 110 (12).

Sakata, E., Yamaguchi, Y., Kurimoto, E., Kikuchi, J., Yokoyama, S., Yamada, S., Kawahara, H., Yokosawa, H., Hattori, N., Mizuno, Y., et. al. (2003) EMBO Reports 4, 301-306.

The Parkinson Disease Study Group. Effect of deprenyl on the progression of disability in early Parkinson's disease. The New England Journal of Medicine 1989;321:1364–1371.

Verdu, J., Buratovich, M. A., Wilder, E. L. & Birnbaum, M. J. (1999) Nature Cell Biology. 1, 500-506.

Wilson, M. A., Collins, J.L., Hod, Y., Ringe, D. & Petsko, G. A. (2003) Proceedings of the National Academy of Sciences USA 100, 9256-9261

Wittmann, C. W., Wszolek, M. F., Shulman, J. M., Salvaterra, P. M., Lewis, J., Hutton, M. & Feany, M. B. (2001) Science 293, 711-714.

Yang, Y., Gehrke, S., Haque, M. E., Imai, Y., Kosek, J., Yang, L., et. al. (2005). Inactivation of Drosophila DJ-1 Leads to Impairments of Oxidative Stress Response and Phosphatidylinositol 3-Kinase/ Akt Signaling. Proceedings of the National Academy of Sciences of the United States of America , 102 (38), 13670-13675.

Zhang, W., Wang, T., Qin, L., Gao, H.-M., Wilson, B., Ali, S. F., et. al. (2004). Neuroprotective effect of dextromethorphan in the MPTP Parkinson's disease model: role of NADPH oxidase. The FASEB Journal , 589-591.