Mitochondrial Aconitase Inactivation in MPTP Neurotoxicity

Manisha N. Patel, Ph.D.
National Jewish Medical and Research Center, Colorado

Abstract

Many scientists today think that free radicals produced by oxidative stress are part of the cause of PD. Along this vein, Dr. Manisha N. Patel (National Jewish Medical and Research Center, Denver) hypothesizes that damage caused by free radicals inactivates a needed protein called aconitase, found in mitochondria. Using an MPTP-mouse model of parkinsonism, she and her group will try to determine if the neurotoxin inactivates mitochondrial aconitase and if so, can scavenging superoxide radicals with native or synthetic antioxidants protect against this inactivation and thus protect against the toxicity-caused death of neurons? The work also seeks to define the importance of the iron load of mitochondria that has been implicated by others as a cause of neuronal death in parkinsonism.

Progress Report (as of 3/2003)

The best animal model of parkinsonism in mice available today is that made by the administration of the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Dr. Manisha Patel and his team at the National Jewish Medical/Research Center (Colorado) hypothesized in their grant proposal that the toxin selectively inactivates a mitochondrial enzyme, aconitase, in the substantia nigra, resulting in increases of iron that accumulates and contributes to free-radical damage and thus neurodegeneration. They derived data to support these hypotheses using both wild-type (normal) and transgenic mice, finding that mitochondrial and cell function were compromised and that this resulted in neuronal death. Now they and others will work to translate these data into applications to the human disorder, PD.


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