Tuesday Jul 9th, 2002
by Anne Jacobson
Investigator: David S. Park
Neurodegenerative disorders involve the premature or aberrant loss of vulnerable neurons, often through programmed cell death, or apoptosis. Researchers today revealed new therapeutic targets aimed at preventing neuronal suicide.
Drugs that block apoptosis could inhibit neuronal degeneration and ultimately slow or halt progression of neurodegenerative disorders such as Parkinson's disease (PD), said Michael Saporito of Cephalon Inc., in West Chester, Pennsylvania. Saporito chaired a session on unique molecular targets for disease intervention.
One of the best models for PD involves treating animals with a mitochondrial toxin called 1,2,3,6-tetrahydropyridine (MPTP). The toxin produces a clinical phenocopy of human PD, although its pathology is slightly different. MPTP destroys nigrostriatal neurons throughout the nigra region of the brain indiscriminately, and typical Lewy bodies are not produced.
In both the MPTP animal model of PD, and in human disease, calcium-dependent proteases, or calpains, play a key role in the loss of dopamine neurons, according to work presented by David S. Park, assistant professor of molecular medicine at the University of Ottawa.
When Park administered MPTP to mice in vivo, he observed a progressive increase in calpain-related proteolytic activity in dopamine neurons in the substantia nigra. By inhibiting calpains - either through infusion of a calpain inhibitor or over-expression of the endogenous calpain inhibitor, calpastatin - the team triggered a striking decrease in MPTP-induced neuronal apoptosis.
Inhibiting calpain protected against neurodegeneration in two other ways. First, the treatment decreased motor deficits associated with MPTP treatment. Second, it prevented MPTP-induced post-synaptic changes in the striatum.
Interestingly, dopamine levels in the striatum did not mediate this protection, suggesting that protection of the substantia nigra alone may improve behavioral outcomes.
To further characterize the role of calpain in human PD, Park and his colleagues used immunohistochemistry to evaluate human post-mortem midbrain samples for patterns of calpain activity. Though tissues from PD patients showed evidence of significant calpain activation in the substantia nigra, the researchers did not find elevated calpain in tissues from control patients.
"Taken together, our findings suggest a potentially novel link between calpain activity in the MPTP model of Parkinson's disease and the etiology of Parkinson's disease in humans," Park said.
Drugs that interfere with calpains, caspases, and the JNK signaling pathway - which is also implicated in apoptosis - are all titillating targets for drug therapy, said Robert E. Burke, a professor of neurology and pathology at Columbia University in New York.
Both medical and surgical therapies now available are aimed toward relieving
symptoms, but none is directed at preventing the neurodegenerative process,
Burke said, adding therapies that prevent the neurodegenerative process
are "the Holy Grail of drug development."
© Elsevier Science Limited 2002