CNS program participants gather at NIEHS
By Ernie Hood
The NIEHS Centers for Neurodegeneration Science (CNS) program held its fourth annual meeting May 3-4 at NIEHS, with approximately 65 scientists and trainees from the centers (see text box) joining scientists and administrators from the Institute.
Established in 2008 to build upon the success of the previous Collaborative Centers for Parkinson’s Disease Environmental Research program, the five-year CNS initiative funds integrated basic and clinical research to elucidate the environmental and genetic interactions that contribute to the development of Parkinson’s disease (PD) and related neurodegenerative diseases. The highly collaborative, cross-disciplinary work being conducted at the centers, located at Emory University, University of California, Los Angeles (UCLA), and the Sanford-Burnham Medical Research Institute, has spawned new understanding of the role of the environment in the pathogenesis of neurodegenerative diseases, as well as the discovery of important new biomolecular mechanisms, therapeutic targets, and treatment modalities.
The annual meeting gathers center directors, project investigators, trainees, and NIEHS scientists to highlight findings emerging from each center and to provide a forum for discussion of current trends in the field. “It’s very important for the centers to get together and update each other on what’s going on and what progress has been made in the year,” said meeting co-organizer Annette Kirshner, Ph.D., one of the NIEHS scientific program administrators who oversee the CNS program. “It’s also a wonderful opportunity to start establishing collaborations between and among centers, and sometimes all three of them have a hand in something.”
At the meeting, each of the centers reported on the progress of their research projects since last year’s gathering. They all have projects exploring the role of exposures to environmental toxicants, particularly pesticides, such as rotenone, maneb, and paraquat, in the loss of dopaminergic neurons in the brain’s substantia nigra region, which leads to PD.
The Emory center, directed by Gary Miller, Ph.D., is working to improve understanding of how environmental toxicants disrupt dopamine homeostasis, mitochondrial function, and redox balance in the substantia nigra, and how the affected neurons respond to such insults. Miller and his colleagues have also developed a mouse model genetically engineered to produce low amounts of VMAT2, a protein used in dopaminergic neurons to clear away excess dopamine. Inhibition of the protein can lead to PD. The team also reported significant progress in the use of high-resolution metabolomics to identify blood biomarkers of PD risk.
At the UCLA center, co-directed by Mary-Francoise Chesselet, M.D., Ph.D., and Beate Ritz, M.D., Ph.D., research on PD and the environment runs a bidirectional gamut, from cell-based experiments through other model organisms such as Drosophila, zebrafish, and mice, and into humans, as well. The group has identified an association between exposure to specific pesticides and increased risk of PD, in an exceptionally well-characterized patient cohort in the agricultural region of California’s Central Valley. An animal model project has shown that traumatic brain injury causes progressive death in dopaminergic neurons, and when combined with later pesticide exposure, a synergistic effect leads to a substantially greater risk of developing PD. The team confirmed the phenomenon in the Central Valley human cohort.
Researchers at the Sanford-Burnham center, directed by Stuart Lipton, M.D., Ph.D., are studying the effects of environmental stress, represented by oxidation and S-nitrosylation, on PD-related proteins, and are working to develop new therapeutics with high-throughput screening of chemical libraries using platforms of lower organisms such as Drosophila and in recombinant and cell-based screens. The hits derived from those assays are then further tested in human embryonic stem cell (hESC)-derived dopaminergic neurons. The hESC model is also being used to study developmental vulnerability to PD-related abnormal proteins or oxidative/nitrosative stress as the stem cells differentiate into dopaminergic neurons.
(Ernie Hood is a contract writer for the NIEHS Office of Communications and Public Liaison.)
Training and CNS
In addition to the scientific proceedings, the meeting represented a unique opportunity to enhance training among the centers’ members, many of them junior investigators at an early stage in their careers. According to leaders of the initiative, training and career development are indispensable elements of the CNS program, for some very solid reasons.
“What’s happening in science these days is that we’re graying out, and for a variety of reasons it’s not been easy to get the next generation up the ladder to start replacing all of us graying-out people,” said Kirshner. “Also, trainees very often get trained in disciplines that were practically nonexistent when their mentors started out. So trainees are an integral part of the research projects, and that kind of diversity is needed.”
Miller noted that the center model provides a unique forum for effective training. “When you have this sort of center model, you have graduate students and postdocs [with] four or five mentors, because they’re collaborating between those groups,” he said. “So it creates a much richer training environment for them, because they’re exposed to tools and approaches that they otherwise wouldn’t have, and it’s done in an organized fashion. So I think that’s really helped out a lot of our trainees to see this collaborative, interactive nature, which is really the wave of the future in science. And seeing how it works in practice as a trainee is really helpful for that.”
Chesselet cited the long-term professional relationships formed during training and the use of training opportunities to help attract early-stage researchers to the environmental health sciences. “There are two aspects to training. One is the trainees in our labs, and I can tell you from the experience that I had with the previous iteration of these centers, I am still in contact with trainees from that time, who are now young faculty, and I’m still having a mentoring role in development of their careers, because we met when they were young trainees.”
“I hope that the same will happen with the current trainees,” she continued. “In addition, one of the trainees from my lab is now a postdoc in another lab in the consortium, and that it is a continuation for him, but he is also learning a lot of new things. Also, a lot of these young scientists would never have paid attention to environment if they had not been brought in and seen not only what’s done in our lab, but in the center and then among the other c enters. If you catch people very early and give them passion for a particular field of science, they are much more likely to stay with it, and that’s really important.”