Protective Mechanisms Against Apoptic Neurodegeneration in the Substantia Nigra.
Annual rept. 1 Sep 98-31 Aug 99
MASSACHUSETTS UNIV MEDICAL SCHOOL WORCESTER
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The overall goal in this proposal is to understand the mechanisms by which neurotoxicity and excitotoxicity destroy cells in the substantia nigra. Our hypothesis to test this idea is that c-JUN kinase JNK, specifically the subtype JNK3, mediates degeneration of substantia nigra neurons after exposure to MPTP or glutamate excitotoxicity. Results in the first year of the project indicate that glutamate agonists at NMDA and kainate receptors increase the biological activity of INK in the basal ganglia cultured striatal neurons. The subtype JNK3 accounts for most of the JNK activity. Striatal neurons from JNK3 knockout mice lacked most of the biological activity of JNK after glutamate agonist treatment and the size of the JNK responsible for the biological activity corresponded to JNK3. We also observed another, larger protein complex with JNK activity. In vivo studies revealed that the MPTP-induced neurotoxicity in wild-type mice was ameliorated in JNK3 knockout mice, but JNK1 and JNK2 offered even greater neuroprotection. Altogether, these year 1 results implicate JNK3 as the principal JNK target of glutamate stimulation in the striatum and JNKs as important mediators of MPTP induced neurotoxicity.