BARCELONA—Increasing evidence that programmed cell death is the cause of many neurodegenerative disorders—and mounting evidence of the involvement of caspases in this process—have influenced research in the prevention and treatment of Parkinson's disease and other neurologic disorders. Robert Burke, MD, of the Departments of Neurology and Pathology at Columbia University in New York City, explained that the three known pathways to cell death, some of which may overlap, all lead to the activation of the caspases, which cleave at an aspartate.

Most studies of cell death in neurons, he told a session of the Sixth International Congress on Parkinson's Disease and Movement Disorders, have revolved around the so-called "intrinsic pathway." In this pathway, cytochrome c is released from the mitochondria, leading to activation of a caspase cascade, which can result in cell death.

CASPASE-MEDIATED CELL DEATH?

"Of the 14 human caspases now known," said Dr. Burke, "caspase-3 has been the most studied with regard to apoptosis in the brain." It has been shown in animal models that caspase-3 can be activated in the brain by axotomy, ischemia, or trauma, he said.

Caspase-9 is suspected of regulating cell death in neurons. Caspase-9 knockout mice have shown neuronal overgrowth in the brain. This overgrowth is believed to be the result of reduced apoptosis during development—a time when, in humans and animals, excess neurons are ordinarily culled, said Dr. Burke.

While some morphologic studies have not supported the role of apoptosis in Parkinson's disease, other in vitro and in vivo models of neurodegenerative diseases indicate that apoptosis plays a role in the etiology of neurodegenerative diseases, Dr. Burke explained. In Alzheimer's disease, for example, while apoptosis has not yet been definitively observed, there is evidence for abnormal expression of cyclin-dependent kinase 5, which has been implicated in programmed cell death. In triplet-repeat diseases such as Huntington's disease, there is also evidence that caspases are involved in programmed cell death, although this has not been demonstrated morphologically.

Due to the lack of morphologic evidence, he suggested that further studies of programmed cell death might better rely on biochemical assessments in determining the role of apoptosis in neurodegenerative disease.

Dr. Burke also suggested that further knowledge of programmed cell death may lead to improvements in the viability of cell transplants for Parkinson's disease and other neurodegenerative diseases.

"Knowledge of the role of caspases in cell death could lead to the production of anticaspase drugs. However, "it might instead be better to block activities far upstream from caspase involvement in the cell death pathway, before too much damage is done to the cell," Dr. Burke added.

Working further upstream, though, such as with the transcription factor c-jun, which is involved in the beginning of the caspase cascade, could be a two-edged sword because c-jun is also involved in oncologic processes.

TARGETING CELLS: A LESS OPTIMISTIC VIEWPOINT

Commenting on Dr. Burke's presentation, session chair Serge Przedborski, MD, of Columbia University, said, "During development, we have too many cells and we scale down to the number we need for proper brain functioning, and that involves exactly the same mechanism as in animals, for instance, which undergo morphogenesis. This involves a caspase mechanism which seems to remain quiescent during adult life, but which—by an unknown mechanism—may be reactivated later in life and participate in neurodegeneration."

Dr. Przedborski said that his group is less optimistic about the direct targeting of cells doomed to die. However, he noted that the caspase mechanism is certainly worth studying, as is the role played by the diminished mitochondrial function, which has also been implicated in programmed cell death.

—Jean McCann

Suggested Reading
Jeon BS, Kholodilov NG, Oo TF, et al. Activation of caspase-3 in developmental models of programmed cell death in neurons of the substantia nigra. J Neurochem. 1999;73:322-333.
Li M, Ona VO, Guegan C, et al. Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science. 2000;288:335-339.
Oo TF, Henchcliffe C, James D, Burke RE. Expression of c-fos, c-jun, and c-jun N-terminal kinase (JNK) in a developmental model of induced apoptotic death in neurons of the substantia nigra. J Neurochem. 1999;72: 557-564.
Pennathur S, Jackson-Lewis V, Przedborski S, Heinecke JW. Mass spectrometric quantification of 3-nitrotyrosine, ortho-tyrosine, and o,o-dityrosine in the brain tissue of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice, a model of oxidative stress in Parkinson's disease. J Biol Chem. 1999;274:34621-34628.
Przedborski S, Vila M, Jackson-Lewis V, Dawson TM. Reply: a new look at the pathogenesis of Parkinson's disease. Trends Pharmacol Sci. 2000;21:165.

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