When telephone lines go down, or Internet connections are lost, our communities temporarily come to a halt. What if something similar were found to be happening in Parkinson's? This is the focus of Dr. Schmitz and her team at the PDF Research Center at Columbia University Medical Center.
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Lloyd A. Greene, Ph.D.
This article originally appeared in the Winter 2010 edition of PDF's quarterly newsletter, News & Review.
As a member of the group funded by the Parkinson’s Disease Foundation’s (PDF) center grant to Columbia University Medical Center, Lloyd A. Greene, Ph.D., and his team — Elizabeth Ryu, Ph.D., Cristina Malagelada, Ph.D., Oren Levy, M.D., Ph.D., and Neela Zareen — are focused on understanding both how neurons die in Parkinson’s disease (PD) and how to prevent the process.
Recently, this team examined tens of thousands of genes in a laboratory model of Parkinson’s. Several of the genes were overexpressed, with levels far higher than those present in healthy neurons. They found that one gene — RTP801 — was more overexpressed than any of the others. Drs. Greene and Malagelada then asked the questions: Is RTP801 also overexpressed in people living with Parkinson’s? And does it therefore play a role in neuron death in PD?
They found that the answer to both of these questions was yes. RTP801 was overexpressed in people with PD and can directly cause neuron death. Then, Dr. Levy found that alpha-synuclein, a gene already known to be linked to some cases of PD, actually causes high expression of RTP801.
But just how does RTP801 cause neuron death in PD? The answer is important because it might reveal clues about potential therapies. Back in the lab, Drs. Greene and Malagelada discovered that excess RTP801 blocks the activity of Akt, a key cellular enzyme, from doing its job of protecting neurons. They found a similar result in people who had PD. At this point, their research intersected with that of their colleague Robert Burke, M.D. Dr. Burke found that in animals with a form of Akt that was resistant to the actions of RTP801, neurons were protected, even from a toxin that mimics PD. The convergence of these two pathways demonstrates the importance of Akt as a target for PD therapeutics.
Armed with this new knowledge, Dr. Greene’s team has begun to address the most important question: Is there a way to stop this process and slow the progression of PD? They found a lead with a drug called rapamycin, an immunosuppressant used to treat kidney transplant recipients. In the lab, it protects neurons from toxins that mimic PD. Working with colleagues Serge Przedborski, M.D., Ph.D., and Vernice Jackson-Lewis, Ph.D., they have also found that rapamycin protects dopamine neurons in experimental animal models of PD. Dr. Greene says that this approach may not necessarily be practical as a PD therapy because rapamycin severely compromises a person’s immune system. But his team hopes that understanding how rapamycin works may open the door to exploring other potential treatments.
As Dr. Greene sums it up, “our results reflect the achievements of a team of bright scientists, at various stages of their careers, all intently focused on Parkinson’s disease. Their shared knowledge, creativity and collaboration, along with their dedication, enables our research progress and advances our understanding of the disease. I am grateful to PDF for helping to make this possible. ”
Dr. Greene is Professor of Pathology and Cell Biology at Columbia University. In FY2010, PDF will provide over $2.7 million to support the Columbia University Center Grant.