Office Phone: 318-675-5163
Laboratory Phone: 318-675-5170
Office Fax: 318-675-5180
B.F.A., 1979, Tufts University
B.S., 1981, Union College
Ph.D., 1988, California Institute of Technology
Postdoctoral, 1988-93, Stanford University
Alpha Synuclein and Parkinson’s disease; alpha synuclein and melanoma; vesicle trafficking; molecular bases of disease.
a-Synuclein and Parkinson disease
We use several organisms (yeast, mice and human cells) to study the mechanism of toxicity of the human Parkinson disease-associated protein a-synuclein (a-syn). a-Syn is an intrinsically unfolded protein of unknown function that is the main protein component of Lewy bodies, which are proteinaceous cytoplasmic inclusions in dopamine-producing neurons in individuals who suffer from PD. High expression levels of a-syn or posttranslational modifications of the protein are thought to convert a-syn from a non-toxic protein into a toxic one. There is increasing evidence that the toxic conformation of a-syn is a prion: it acts as a template or seed that converts non-infectious a-syn monomers into infectious oligomers. Examples of ongoing projects include:
(1) a-Syn and cell signaling: We have shown that a-syn disrupts mitogen-activated protein kinase (MAPK)-controlled stress signaling in yeast and human cells, which results in inefficient cell protective responses and cell death. a-Syn is a substrate of the yeast (and human) polo-like kinase Cdc5 (Plk2), and elevated levels of a-syn prevent Cdc5 from maintaining a normal level of GTP-bound Rho1, which is an essential GTPase that regulates stress signaling. The nine N-terminal amino acids of a-syn are essential for the interaction with polo-like kinases. We are testing the ability of a-syn to disrupt cell signaling in human cells in culture and in mice.
(2) a-Syn intra-cellular trafficking and Lewy body formation: In eukaryotic cells, wild-type a-syn transits through the endoplasmic reticulum and Golgi apparatus on route to the inner leaflet of the plasma membrane. In neurons, a-syn is thought to promote the fusion of presynaptic vesicles with the presynaptic membrane. We have found that the trafficking of a-syn through the ER is exquisitely sensitive to the level of certain cellular phospholipids, and we are investigating how changes in phospholipid homeostasis alter, and in some cases blocks, a-syn transit through the ER. This work has implications to the mechanism of Lewy body formation.
(3) a-Syn and iron homeostasis: Many studies over the last 10 years have found a link between a-syn and iron homeostasis. Red blood cells contain relatively high levels of a-syn as well as neurons. Because many of the genes involved in iron homeostasis in human cells are also found in yeast, we are using yeast to investigate the connection between a disruption of cellular iron homeostasis and a-syn toxicity. The findings from yeast are being tested in worms and human cells.
a-Synuclein and melanoma
It is curious that individuals with melanoma (who live) have a 2-fold higher risk of being afflicted with PD than age-matched healthy controls. And it works the other way, that is, individuals with PD have a significantly higher risk of developing melanoma than age-matched individuals without PD. Melanocytes, like dopaminergic neurons, express a-Syn. Melanocytes, like dopaminergic neurons, synthesize a pigment (melanin). Some of the most aggressive melanomas also express very high levels of a-Syn, as if somehow a-Syn promotes growth. Experiments are underway in the Witt lab to decipher the function of α-syn in melanoma.
All Publications: PubMed