Quinones and Other Reactive Oxygen Species in Neurobiologic, Apoptotic, and Neurotoxic Processes

Re: Free radicals and dopamine system degeneration

Jean Lud Cadet, M.D.
jcadet@intra.nida.nih.gov

On Tue Dec 15, Richard M. Kostrzewa wrote
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>The review by D. Offen and E. Melamed summarizes some of the newer studies that implicate apoptotic mechanisms in nigrostriatal neuronal degeneration in Parkinson's disease. Your findings give evidence that the proto-oncogene bcl-2 is important in protecting against oxidative damage during dopamine metabolism, and that an important mechanism is prevention of apoptotic processes. This is an intriguing finding. Let me ask if there are likely to be families of prodeath and antideath genes that are continually in competition for preventing or promoting cell death? Do you foresee that the next generation of anti-Parkinsonian drugs will be those that target such genes?

From Cadet

Those are interesting points. Professor Offen's review and some of the work from that laboratory support the idea that cell death related genes might be perturbed in patients who suffer from PD. The family of bcl-2 related genes which include both pro-apoptotic (Bax, Bad, Bcl-Xs etc) and antiapoptotic (bcl-2, bcl-XL etc) genes meet the requirements for homeostatic balance. For example, overexpression or forced dimerization of bax lead to cell demise whereas overexpression of bcl-2 confers resistance to cell death. There is also evidence that the caspases are intimately connected to these pathways because knockout of caspase 3 or 9 lead to significant development abnormalities in mice.

If the idea of perturbations in bcl-2 in neurodegenerative disorders is correct, it should be possible to develop specific treatments that mimic the mode of action of these proteins. Even if the idea is incorrect, administration of bcl-2 mimics should provide an excellent way of delaying the progression of disorders such as Parkinson's disease.

Tue Dec 15