Genetic and Epigenetic Mechanisms Underlying Acute and Delayed Neurodegenerative Consequences of Stress and Anticholinesterase Exposure
Abstract
To characterize neuropathological consequences of excess acetyicholinesterase (AChE), we employed transgenic mice developed under previous US Army support. These mice demonstrated association between such excess and adverse responses (in brain and intestine) to pyridostigmine and diisopropylfluorophosphonate. The stress-associated "readthrough" AChE-R variant was seen also in progenitor blood cells, suggesting its use as a surrogate marker for anti-AChE responses. Moreover, AChE-R accumulates in the brain following head injury, its pre-injury excess exacerbates damage, and its antisense suppression improves survival and recovery. Using a 2-hybrid yeast screen we discovered a previously unknown interaction of AChE-R with RACK 1, a protein kinase cargo protein involved in signaling processes. Animals carrying a tetracycline-inducible anti-AChE antisense sequence are being characterized for further studies of these interactions. At the extended promoter of the A CHE gene, we found a 4 bp deletion that over-induces transcription and hypersensitivity to pyridostigmine through impairment of HNF3beta interaction, and discovered a novel mutation that disrupts the glucocorticoid binding site. Finally, we found AChE-R-specific inhibitor interactions in mouse brain that reflect the specific increase in the AChE-R variant after psychological stress., The AChE-R variant thus emerges as the key scavenger and acetylcholine- hydrolzing agent in several mammalian tissues under various stress insults.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2000
- Accession Number
- ADA384368
Entities
People
- Hermona Soreq
Organizations
- Hebrew University of Jerusalem