Serge Przedborski, Ph.D.

Research Summary
The Molecular Basis of Neurodegeneration and Therapeutic Strategies

Research is geared toward unraveling the molecular basis of neurodegeneration and devising therapeutic strategies to hamper the processes that cause neuronal death. To that end, we have concentrated our research efforts on the MPTP mouse model of Parkinson's disease (PD) and on the mutant superoxidedismutase-1 (mSOD1) mouse model of amyotrophic lateral sclerosis (ALS). Work in our 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 shown 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. Cell death is likely to result not only from these injuries, but also from apoptosis. 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, the expression of key molecular apoptotic factors is 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. 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.

1. Przedborski, S., Jackson-Lewis, V., Yokoyama, R., Shibata, T., Dawson, V.L., Dawson, T.M. (1996). Role of neuronal nitric oxide in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced dopaminergic neurotoxicity. Proc. Natl. Acad. Sci. USA, 93: 4565-4571.

2. Kostic, V., Jackson-Lewis, V., De Bilbao, F., Dubois-Dauphin, M., Przedborski, S. (1997). Bcl-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis. Science, 277: 559-562.

3. Liberator, G., Jackson-Lewis, V., Vukosavic, S., Mandir, A.S., Vila, M., McAuliffe, W.J., Dawson, V.L., Dawson, T.M., Przedborski, S. (1999). Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. Nature Med., 5: 1403-1409.

4. Vila, M., Jackson-Lewis, V., Vukosavic, S., Djaldetti, R., Liberatore, G., Offen, D., Korsmeyer, S.J., Przedborski, S. (2001). Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Proc. Natl. Acad. Sci. USA, 98: 2837-2842.

5. Wu, J.-L., Vila, T., Teismann, V., Choi, I., Przedborski, S.(2002). Blockade of microglial activation is neuroprotective in the1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. J. Neurosci., 22: 1763-177.

6. Smith PD, Crocker SJ, Jackson-Lewis V, Jordan-Sciutto KL, Hayley S, Mount MP, O'Hare MJ, Callaghan S, Slack RS, Przedborski S, Anisman H, Park DS. Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13650-5.

1. Nitric oxide and protein nitrotyrosine in the the MPTP model
Specific Aim (SA)-Compare the effects of MPTP on SN DA neurons of mutant mice deficient in neuronal, inducible, or endothelial NO synthase (NOS), the three isoforms of NOS. To demonstrate the production of peroxynitrite following MPTP administration, SA-II will quantify striatal and midbrain levels of nitrotyrosine, a stable fingerprint of peroxynitrite's deleterious effects on proteins, at different time-points and doses of MPTP. The requirement for superoxide, NO, and MPTP's active metabolite, 1- methyl-4-phenylpyridinium in protein nitrotyrosine formation, as well as its specificity for DA neurons will also be examined. To define the cell groups and organelles preferentially tyrosine-nitrated, SA-III will ascertain the cellular and subcellular distribution of nitrotyrosine immunoreactivity in the mouse midbrain after MPTP administration. To examine the potential biological consequences of protein tyrosine nitration, SA-IV will assess whether candidate proteins, tyrosine hydroxylase and manganese superoxide dismutase, are nitrated after MPTP administration. The catalytic activity of these enzymes and the search for other proteins that are tyrosine-nitrated after MPTP administration will also be undertaken.
National Institute of Neurological Disorders and Stroke
4/1/1998-3/31/2004

2. Proinflammatory enzymes in amyotrophic lateral sclerosis
This proposal is submitted to pursue our investigation of the pathogenesis of amyotrophic lateral sclerosis (ALS) using transgenic mice expressing the glycine-93 yields arginine mutant copper/zinc superoxide dismutase (SOD1G93A). This proposal contains a comprehensive set of experiments, which should provide insights into the role of iNOS, hypochlorous acid and its synthesizing enzyme MPO, as well as into Cox-2 in transgenic SOD1G93A mice. It should also shed light onto the mechanisms of neurodegeneration in ALS.
National Institute of Neurological Disorders and Stroke
8/01/2001-7/31/2005

3. Synuclein and nigral dopaminergic neuron degeneration
This proposal is submitted to pursue our exploration of the pathogenesis of Parkinson's disease (PD). Pertinent to this goal, we have found that synuclein expression is increased in the mouse midbrain after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, a toxin that damages the substantia nigra pars compacta (SNpc) as seen in Parkinson's disease. Mutations in the alpha synuclein gene are associated with the development of a familial form of PD. However, to date, the link between synuclein and SNpc neurodegeneration is unknown.
National Institute of Neurological Disorders and Stroke
5/1/1999 - 4/30/2004

4. Experimental Therapeutic Strategies for ALS
This proposal focuses on the role of inflammation in the pathogenesis of and therapeutic options for amyotrophic lateral sclerosis (ALS) using transgenic mice expressing the glycine-93--> arginine mutant copper/zinc superoxide dismutase (SOD1G93A). Pertinent to this goal, first, we have shown that content of pro-inflammatory prostaglandin PGE2 is increased in spinal cords of affected transgenic SOD1 G93A mice.
National Institute of Neurological Disorders and Stroke
12/01/2002-11/30/2007

methylphenyltetrahydropyridine, neural degeneration, neurotoxin, nitric oxide, nitrogen compound, substantia nigra, tyrosine, Parkinson's disease, disease /disorder model, enzyme activity, manganese, molecular pathology, nitric oxide synthase, oxygenase, peroxynitrite, superoxide, superoxide dismutase, dopamine, nerve /myelin protein, apoptosis, brain metabolism, gene mutation, phosphoprotein, posttranslational modification, PC12 cell, immunoprecipitation, in situ hybridization, laboratory mouse, transgenic animal mouse