Statement of Goals
W. Kaya Erbil
I would like to apply my training in the fundamental science of chemistry to advancing the field of neurobiology. While in graduate school, I have focused on the physiological functions that nitric oxide (NO) plays in the cell. I am particularly fascinated by the dual role that NO plays in the biology of mammals, where it is both a cytotoxic agent and a key signaling species. The least understood functions of NO in biology are in the central nervous system (CNS). For this reason, I have become extremely interested in learning more about the field of molecular and cellular neuroscience, particularly research efforts that seek to elucidate mechanisms of neurodegenerative disease. A question of interest to me is how the chemistry of the brain is altered during the course of neurodegeneration, especially in protein misfolding diseases such as PD. For example, basic and clinical PD research efforts highlight reactive oxygen species (ROS) and reactive nitrogen species (RNS) such as NO as essential molecules in the pathology of the disease (1, 2). More specifically, NO may participate in a “positive feedback toxic cycle” that promotes lesions of dopaminergic neurons (3). While recent progress highlights effects of NO in PD progression, its exact role in the etiology of the disease remains unknown at present (4).
I plan to dedicate my next three years of research to the elucidation of mechanisms of neurodegeneration in gain of toxicity protein misfolding diseases as a post doctoral researcher in the laboratory of Susan Lindquist of the Whitehead Institute at M.I.T. I am interested in the neurodegeneration research initiatives of the Lindquist laboratory for the following reasons. First, I recently read two papers by the Lindquist group (5) and the research group of Thomas Südhof that provide insight into the cellular functions of alpha synuclein (6). These studies stand out because they suggest a molecular mechanism by which genetic polymorphisms in a population may underlie secretory pathway defects responsible for cognitive dysfunction. Second, in February 2008 I also attended a talk by William Wickner of Dartmouth where he described his cell-free yeast vesicle fusion assay. His talk struck me because this assay facilitates enzymology studies of the cellular components that mediate vesicle fusion, but in a setting much closer to that of a natural cell than can be accomplished with artificial vesicle systems (7). I would like to learn how processes such as membrane fusion in vertebrate neurons parallel those observed in yeast in a comparable level of detail. Wickner’s works led me to read the Lindquist group’s paper entitled “The Parkinson’s disease protein alpha-synuclein disrupts cellular Rab homeostasis” (8). This and other recent papers describing studies of the cellular function of alpha synuclein via the use of yeast genetic methods intrigued me because they highlight that a yeast cell provides a high throughput way to ask questions about neurodegeneration (9, 10). A key link between the yeast cell and brain cells is that many of their proteins are ancient and are conserved through evolution (11). Lastly, future efforts in the Lindquist lab will utilize the yeast cell as a platform upon which to develop and test hypotheses regarding molecular pathways and networks in higher models of neurodegeneration (eg. worm, fly, and rat) (5). Classic studies, including those indicating conservation of the “heat shock” response between the fly and yeast encourage the view that molecular networks identified in yeast can reflect the mode of action of metazoan cells (12). I hope to use my knowledge of chemistry, supplemented by the understanding of the brain and nervous system that I anticipate gaining if given the opportunity to attend the Neurobiology course, to contribut to a molecular understanding of PD.
One of my chief goals is to understand the molecular interactions that occur between glia and neurons during the states of health and states of disease in the brain (13). One specific type of such interaction is the exchange of molecular signals such as ROS and RNS between microglia and neurons during dopaminergic cell death in mammalian models of PD. For example, neuroinflammation via activation of microglia and oxidation/nitration of α-synuclein are linked to dopaminergic neurodegeneration in a mouse model of PD (3). While recent progress in the field of molecular and cellular neuroscience highlights the importance of ROS and RNS to PD progression, much remains to be learned. Because newly developed molecular tools from the field of chemical biology facilitate the direct imaging of these substances in vivo, neuroscience is poised to learn more about the biological functions of ROS and RNS in the brain, as Tsien and collaborators have done with Ca2+ signaling in the cell (14, 15). In order to rigorously answer questions about neurodegeneration, biochemical and pharmacological approaches must be utilized in concert with genetic and physiological tools and methods. In the next three years, I hope to complement my training in chemistry with training that will enable me to answer specific questions about physiological and biomolecular mechanisms. I am applying to the Marine Biological Laboratory (MBL) summer course entitled Neurobiology because I believe it is the best way to start advancing this goal.
References are provided on the supplemental page entitled “Statement of Goals: References.”
Statement of Goals: References
W. Kaya Erbil
1. Beal, M.F. (1998). Excitotoxicity and nitric oxide in parkinson’s disease pathogenesis. Ann. Neurol. 44:S110-S114.
2. Giasson, B.I., et al. (2000). Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290:985-989.
3. Gao, H., et al. (2008). Neuroinflammation and oxidation/nitration of alpha synuclein linked to dopaminergic neurodegeneration. J. Neurosci. 28:7687-7698.
4. Dawson, T.M. and Dawson, V.L. (2003). Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302:819-822.
5. Cooper, A.A., et al. (2006). Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science 313:324-328.
6. Chandra, S., Gallardo, G., Fernandez-Hacon, R., Schluter, O.M., and Sudhof, T.C. (2005). Alpha synuclein cooperates with CSP alpha in preventing neurodegeneration. Cell 123:383-396.
7. Mima, J., Hickey, C.M., Xu, H., Jun, Y., and Wickner, W. (2008). Reconstituted membrane fusion requires regulatory lipids, SNAREs and synergistic SNARE chaparones.EMBO J. 27:2031-2042.
8. Gitler, A.D., et al. (2008). The Parkinson’s disease protein alpha-synuclein disrupts cellular Rab homeostasis. Proc. Natl. Acad. Sci. U S A 105:145-150.
9. Outeiro, T.F. and Lindquist, S. (2003). Yeast cells provide insight into alpha-synuclein biology and pathobiology. Science 302:1772-1775.
10. Willingham, S., Outeiro, T.F., DeVit, M.J., Lindquist, S.L., and Muchowski, P.J. (2003). Yeast genes that enhance the toxicity of a mutant huntingtin fragment or alpha-synuclein. Science 302:1769-1772.
11. Emes, R.D., et al. (2008). Evolutionary expansion and anatomical specialization of synapse proteome complexity. Nat. Neurosci. 11:799-806.
12. Lindquist, S. (1981). Regulation of protein synthesis during heat shock. Nature 293:311-314.
13. Miller, G.W. (2005). The dark side of glia. Science 308:778-781.
14. Grynkiewicz, G., Poenie, M., & Tsien, R.Y. (1985). A new generation of Ca2+ indicators with greatly improved fluorescence properties. J. Biol. Chem. 260:3440-3450.
15. Miller, E.W. and Chang, C.J. (2007). Fluorescent probes for nitric oxide and hydrogen peroxide in cell signaling. Curr. Opin. Chem. Biol. 11:620-625.