Protective Mechanisms against Apoptic Neurodegeneration in the Substantia Nigra
Abstract
The goal in this proposal is to understand mechanisms by which neurotoxicity destroys cells in the substantia nigra. Our hypothesis is that c-JUN kinase (JNK) mediates neurodegeneration in the substantia nigra after exposure to MPTP or glutamate excitotoxicity. In the first year, we examined mice for susceptibility to MPTP induced neurodegeneration. Our results indicated that JNK knockout mice (lacking isoform 1) were resistant to the toxic effects of MPTP, compared to wild-type (WT) mice. Our objective in year 2 was to confirm these results with WT of the same strain background as the JNK knockout mice. Neuroprotection is still evident with a larger group of JNK 1 animals. We also extended the results to JNK 2 knockout and JNK 3 knockout mice. We completed the inbreeding of the 129/B6 mice to form a B6 background (10 generations). Furthermore, we initially proposed to find whether JNK activation of AP-1 regulated gene transcription (through c-JUN phosphorylation) was necessary for JNK mediated cell death. In year 2 we developed a rapid PCR method to detect transcription of luciferase in mice containing an AP-1 dependent luciferase transgene. In year 3, we will complete the studies on the role of JNK isoforms in MPTP induced neurotoxicity in the original 129/B6 and the newly derived B6 strains of mice. We will crossbreed the AP-1 luciferase transgenics with the JNK knockout and then investigate the molecular mechanism of possible protection in the JNK knockout mice.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2000
- Accession Number
- ADA385272
Entities
People
- Neil Aronin
Organizations
- University of Massachusetts