Przedborski Lab

Serge Przedborski has pioneered the investigation of molecular mechanisms of neuronal death in the MPTP model of Parkinson's disease (PD) and in the mutant superoxide dismutase model of amyotrophic lateral sclerosis (ALS). He has demonstrated the importance of the cascade of deleterious events—oxidative stress, inflammation and apoptosis—in the demise of nigral dopaminergic neurons in PD and of spinal cord motor neurons in ALS.

The research conducted in my laboratory is geared toward unraveling the molecular basis of neurodegeneration and devising therapeutic strategies to hamper the processes that cause neuronal death, the source of many debilitating disorders.

To that end, my laboratory has concentrated its research efforts on the MPTP mouse model of Parkinson's disease (PD) and on the mutant superoxide dismutase-1 (mSOD1) mouse model of amyotrophic lateral sclerosis (ALS). For the past decade, we have contributed significantly to the understanding of the molecular mechanism of MPTP neurotoxicity and consequently, the pathogenesis of PD. For instance, this laboratory has demonstrated that following the administration of the neurotoxin MPTP, the demise of the nigral dopaminergic neurons (the hallmark of PD) depends on the production of the reactive species, nitric oxide (NO), which originates in neighboring neurons and glial cells.

We have also demonstrated that NO does not cause damage directly but rather by reacting with another reactive species superoxide to produce peroxynitrite—the actual culprit. We have shown that peroxynitrite, once produced, inflicts severe damage on cell proteins and DNA. It is likely that cell death results not only from these injuries, but from apoptosis as well. Apoptosis, which is a form of programmed cell death, also appears to play a major role in the degeneration of spinal cord motor neurons in ALS. This view is supported by several recent publications from our laboratory. For example, it appears that the expression of key molecular apoptotic factors are altered in transgenic mSOD1 mice in a way that promotes cell death.

Through genetic and pharmacological interventions aimed at alleviating these noxious changes, one of our teams was able to prolong survival and attenuate neuronal death in this mouse model of ALS. They have demonstrated that this beneficial effect is, in part, mediated by the prevention of the release of cytochrome c from the mitochondria, which triggers a cascade of deleterious events implicated in the death of motor neurons.