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SERGE PRZEDBORSKI
ON PUTTING THE BRAKES ON CELL DEATH

For Serge Przedborski, MD, PhD, it is all about the process – how things in the body work. “I'm fascinated by the sequence of events, how things interact with each other – collude, basically – to ultimately reach a certain outcome. I've always been quite interested by processes, in general, things that have a start and go after different steps to an end and a well-defined outcome,” said Dr. Przedborski, Associate Professor of Neurology and Pathology at Columbia University College of Physicians and Surgeons – and this year's winner of the AAN Sheila Essey Award for amyotrophic lateral sclerosis (ALS) research.

The particular well-defined outcome that forms the holy grail of Dr. Przedborski's research is cell death: specifically, the process of programmed cell death that takes place in neurodegenerative diseases like ALS, Parkinson disease, and Alzheimer disease.

“Treating patients, I realized that we'd pinpointed that specific cells were dying, but that was basically as much as we could do. That is why I was attracted to study neurodegeneration,” he told Neurology Today in a phone interview before the AAN Annual Meeting. Dr. Przedborski will receive the Essey Award in a special presentation at the AAN Annual Meeting in April.

STUDY OF APOPTOSIS

Dr. Przedborski is being honored for his pioneering efforts to unravel the molecular basis of neurodegeneration and devising therapeutic strategies to interrupt the processes that cause neuronal death – particularly apoptosis, a form of programmed cell death.

Dr. Przedborski, who has also investigated molecular mechanisms of neuronal death in the MPTP (methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson disease, has identified apoptosis as playing a key role in the degeneration of spinal cord motor neurons in ALS patients as well as in Parkinson and other patients. Much of his work on ALS research has focused on the mutant superoxide dismutase model of ALS.

Dr. Przedborski came to the US after completing his residency in Belgium with a focus on movement disorders. He came to Columbia University for what was to be a two-year fellowship. That was more than a dozen years ago.

“Basically, I fell in love, not only with the US, but with Columbia and the potential for research and clinical work here,” he explained. “The ability to combine clinical work with bench work really satisfied me completely. I'm very excited by clinical work and interacting with patients and treating patients, but in my discipline, if you cannot add an investigative arm to it, you miss some spice to your life and to your practice.”

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Dr. Serge Przedborski: “At the end of the day, I will not be surprised if what would work for these diseases will be a cocktail of interventions, not a single drug to do the job.”

COCKTAIL APPROACH?

Dr. Przedborksi does not envision his apoptosis research, however promising, as providing a complete answer to the puzzles of ALS, Parkinson, and other such diseases. “At the end of the day, I will not be surprised if what would work for these diseases will be a cocktail of interventions, not a single drug to do the job,” he said.

“We've envisioned interventions to target specifically apoptosis to work in ALS, but they probably won't be able to stop the disease. Apoptosis is a late event and the cell is already quite sick at that time. That's why we believe that the anti-apoptotic strategy that we're testing – and we've published, showing benefits in the animal model – has some limits.”

The anti-apoptotic strategy, he predicts, will likely prolong survival in humans as it has in the mouse, but it's unlikely to arrest the disease completely. “We strongly believe that it must be combined with other strategies that act more upstream to the committed point of apoptosis.”

THERAPEUTIC OPPORTUNITIES

What stopping apoptosis can do, he believes, is open the therapeutic window wide enough to allow other strategies to work. “I believe that certain drugs may be very effective, but only if you give them enough time to act. You may allow some cells to hold out just long enough for other drugs to now be effective on them,” Dr. Przedborski said.

And since diseases like ALS and Parkinson are largely sporadic, with little to predict them in advance (at least to date), most patients are not seen and treated until they are already symptomatic and the disease has progressed.

“That's why strategies like this, that do not target the etiology of the disease but rather the mechanisms involved in the demise of cells once the disease has been initiated, that's why those strategies are so valuable.”

A SOURCE OF INSPIRATION

Both as a researcher and as a clinician, Dr. Przedborski finds himself inspired – and sometimes educated – by the intensity of his patients, most of whom read everything they can get their hands on about their disease.

“Even if they don't understand all the details of the science, they're really up to date on what's going on,” he said. “When they come to a center like Columbia, they really expect not only to receive advice on how to adjust their treatment and how they're faring, but also the latest information on what's going on in the field of research.”

Dr. Przedborski's patients frequently inquire about the progress of his laboratory research, wanting to know if it might benefit them down the road or if not them, then other patients in the future.

“They'll ask what I think about recent discoveries and recent papers that have been published.” In many cases, Dr. Przedborski has found them to be fierce advocates for research funding and public awareness. “They're not simply coming to seek medical information. They want to participate almost as a colleague in this fight. Clearly, they are fully committed to finding a cure or better treatment, not only for themselves but for the disease as a whole. They'll offer to contact people on our behalf, to try to sensitize organizations and lawmakers, to increase awareness and press for research funding.”

In one case, the wife of a Parkinson patient whom Dr. Przedborski treated for a number of years was so affected and inspired by his work that she volunteered her chemistry expertise and worked in the lab after her husband died. “She had the impression that by doing so she'd continue the fight of her late husband; she'd remain faithful to him and to his quest.”

DR. SERGE PRZEDBORSKI'S PUBLICATIONS ON NEURONAL DEATH AND ALS

“Increased Expression of the Pro-inflammatory Enzyme Cyclooxygenase-2 in Amyotrophic Lateral Sclerosis,” Annals of Neurology 2001, 49: 176–185.

“Functional Role of Caspase-1 and Caspase-3 in an ALS Transgenic Mouse Model,” Science 2000, 288: 335–339.

“Inducible Nitric Oxide Synthase Upregulation in a Transgenic Mouse Model of Familial Amyotrophic Lateral Sclerosis,” Journal of Neurochemistry 1999, 72: 2415–2425.

“Prolonging Life in a Transgenic Mouse Model of Familial Amyotrophic Lateral Sclerosis,” Science 1997, 277: 559–562.

“Bax and Bcl-2 Interaction in a Transgenic Mouse Model of Familial Amyotrophic Lateral Sclerosis,” Journal of Neurochemistry 1999, 73: 2460–2468.

“Effects of Wild-type and Mutated Copper/Zinc Superoxide Dismutase on Neuronal Survival and L-DOPA-induced Toxicity in Postnatal Midbrain Culture,” Journal of Neurochemistry 1997, 69: 21–33.

KEY FINDINGS OF DR. SERGE PRZEDBORSKI:

  • ♦ Cells dying because of the effects of mutant copper/zinc-superoxide dismutase, which causes a form of familial ALS, exhibit all of the morphological features of apoptotic cells.
  • ♦ Expression of proteins of the Bcl-2 family, which regulate apoptosis, are altered in spinal cords from a mouse model of ALS in ways that promote cell death.
  • ♦ Overexpression of Bcl-2, which blocks apoptosis, prolongs survival and attenuates cell death in a mouse model of ALS.
  • ♦ Several caspases – enzymes responsible for cell death in apoptosis – are activated in the spinal chords in mouse models of ALS.