Universidad de Puerto Rico-Cayey Cayey, Puerto Rico 00736 Alzheimer's and Parkinson's disease common cause Erick G. Rodríguez Cruz Dra. Belinda Román Avilés July 6, 2009 Alzheimer's and Parkinson's disease common cause Abstract: Alzheimer’s and Parkinson’s disease are the two most common progressive neurologic diseases. There is a significant number of patients that have symptoms of both diseases. The purpose of this experiment is to find how neurons degenerate in Alzheimer's and Parkinson's disease, consequently leading to a better understanding of a common cause between these two diseases. With this knowledge I want to discover new and better therapies that could be used to treat both diseases, discover new tools for diagnosing these diseases and find an inhibitor for the enzymes that produce β-amyloid and α-synuclein proteins. By doing this experiment, I will prove my hypothesis that there is a common cause for Alzheimer's and Parkinson's disease. Introduction: Alzheimer's and Parkinson’s disease are the two most common progressive neurologic diseases. This two diseases result in the irreversible loss of neurons in various areas of the brain. They are both caused by the accumulation of proteins. Neither of them have a cure. Alzheimer’s disease is known for being the most common neurodegenerative disease. Alzheimer’s disease symptoms are confusion, memory loss and many others. There are two abnormalities known for being the causes for the dying of nerve cells in Alzheimer's disease. One of them is the plaques formation made of the β-amyloid protein, which accumulates outside the neurons. These proteins are the product of cleavage of the β-amyloid precursor protein. These plaques kill the surrounding neurons. Another cause are the neurofibrillary tangles associated with Alzheimer disease that are made of the microtubular protein tau, which is more abundant in neurons located in the central nervous system, and are less common elsewhere. The function of tau is to regulate the movement of nutrients along microtubules in neurons. In Alzheimer’s disease, hyperphosphorylation of tau occurs, making it bind to itself leading to neurofibrillary tangles. This two abnormalities may be seen in the brains of older people without dementia, but in Alzheimer’s disease they are found in greater quantities in the neocortex and hippocampus. Parkinson’s disease is the second most common neurodegenerative disorder. As in Alzheimer’s disease, in Parkinson’s disease protein aggregates accumulate, but in Parkinson’s disease these proteins kill the neurons in the midbrain that normally release dopamine at synapses in the basal nuclei. Dopamine is a neurotransmitter that has the function of allowing messages to be delivered to the parts of the brain that manage movement. The death of this neurons that release dopamine causes the manifestation of these four symptoms: shaking of legs, hands, arms, jaw, and face; stiffness of the limbs and trunk; slowness of movement; and loss of balance. This symptoms aggravate with time. In Parkinson’s disease, the proteins aggregation that kill the neurons in the midbrain are called Lewy bodies and Lewy neuritis. These aggregates are found inside the nerve cells. The proteins that make Lewy bodies and Lewy neuritis are ubiquitin and α-synuclein. Α-synuclein is found naturally in the brain and controls communication between neurons in the brain but is known to turn toxic and damage cells in patients with Parkinson's disease. A large number of patients have symptoms of both diseases. In an investigation led by Eliezer Masliah at the University of California, San Diego, investigators experimented with β-amyloid and α-synuclein, that are active proteins in both diseases, and concluded that this two chemicals can work together to create a new hybrid protein resulting in a common cause for both diseases to exhibit simultaneously. They also discovered that β-amyloid might promote α-synuclein aggregation by directly interacting with α-syn molecules bound to the membrane and therefore facilitating the formation of more stable oligomers. With this experiment I want to have a better understanding of how neurons degenerate in Alzheimer's and Parkinson's disease. By using this information, I would have a better understanding of a common cause between these two diseases. For this to be done a common cause for Alzheimer's and Parkinson's disease must exist. Methodology: I will make a molecular model in order to understand this protein structure and function relationship. An in vitro experimentation will be done to create the hybrid protein by combining the proteins α-synuclein and β-amyloid. I will insert this hybrid protein into the brains of live mice and make an in vivo experimentation to see its fisical and psicological effects in these mice and compare these effects with the control mice. My control will be mice that have Alzheimer’s disease, mice that have Parkinson’s disease and healthy mice that don’t have any link with these two diseases. I will make a post mortem examination of each of the mice brains by making a brain biopsy and use immunohistochemistry to look for the presence of β-amyloid and α-synuclein aggregates on each of the brains, so I can understand more clearly the effect of this hybrid protein in the brain. For this experiment I will get IACUC permissions for vertebrate experimentations. Future expectations: With this experiment I want to discover new and better therapies for both diseases, therapies that could treat both diseases at the same time. Also by evaluating all my data collected from this experiment, I will find an inhibitor for the enzymes that produce β-amyloid and α-synuclein proteins and discover new tools for diagnosing these diseases. Finally when I have all my work done I would have a better understanding of both diseases, an understanding that I will share with other scientifics to help the world control or even cure these diseases.
Nussbaum, R. and Ellis, C. (2003). Alzheimer's Disease and Parkinson's Disease. The New England Journal of Medicine. 348: 1356-1364 Tsigelny ,I., Crews, L., Desplats, P., Shaked, G., Sharikov, Y., et al. (2008). Mechanisms of Hybrid Oligomer Formation in the Pathogenesis of Combined Alzheimer's and Parkinson's Diseases. PLoS ONE, 3(9): e3135. doi:10.1371/journal.pone.0003135
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