Role of the Stress-Activated Protein Kinase SPAK/JNK Signaling Pathway in the MPTP-Induced Neuronal Death Model of Parkinson’s Disease

Flavell, Richard A., Ph.D.
Yale University, New Haven, CT

Abstract

Dr. Richard A. Flavell will use transgenic mice in his studies of specific enzymes
to determine possible pathways of neuronal death (apoptotic or programmed
cell death vs. necrotic or induced cell death) in dopaminergic neurons.  He and
his colleagues at Yale have done preliminary work to locate specific signals that
may induce the cascade of effects leading to apoptotic neurodegeneration. 
Understanding the apoptotic mechanism(s) should help to develop more
effective therapies that could slow the natural progression of PD by protection
the remaining neurons.

Progress Report (as of 8/2002)

(Yale University) has been studying excitotoxicity using the neurotransmitter glutamate (found in abundance in the brain) that leads to the activation of a type of cell death known as apoptosis. He and his group created a “knock-out” mouse model in which a group of proteins (cJun N-terminal Kinase or cJNK) were genetically deleted. These animals are resistant to excitotoxic neuronal damage. They found that they are partially protected against MPTP-induced damage, seen both biochemically and in motor performance. Additional mouse strains were created to more specifically see these neuronal changes, and the group is now seeking to determine if cyclooxygenase-2 (COX-2), a protein earlier identified as neuroinflammatory, has been lessened or possibly abolished in these mice. These results might well be relevant to the pathophysiology of human PD, indicating targets for drug therapy.


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